Cyclic β-amino acid derivatives as inhibitors of matrix metalloproteases and TNF-α

ABSTRACT

The present application describes novel cyclic β-amino acid derivatives of formula I: 
                 
 
or pharmaceutically acceptable salt forms thereof, wherein ring B is a 5-7 membered cyclic system containing from 0-2 heteroatoms selected from O, N, NR a , and S(O) p , and 0-1 carbonyl groups and the other variables are defined in the present specification, which are useful as metalloprotease and/or as TNF-α inhibitors.

The present application is a divisional application of U.S. applicationSer. No. 09/811,233, filed Mar. 16, 2001 now U.S. Pat. No. 6,743,807,which claims the benefit of U.S. Provisional Application Ser. No.60/190,182, filed Mar. 17, 2000, U.S. Provisional Application 60/233,373filed, Sep. 18, 2000, and U.S. Provisional Application 60/255,539, filedDec. 14, 2000. The contents of each application are incorporated hereinby reference.

FIELD OF THE INVENTION

This invention relates generally to novel cyclic β-amino acidderivatives as matrix metalloproteases and TNF-α inhibitors,pharmaceutical compositions containing the same, and methods of usingthe same.

BACKGROUND OF THE INVENTION

There is now a body of evidence that metalloproteases (MP) are importantin the uncontrolled breakdown of connective tissue, includingproteoglycan and collagen, leading to resorption of the extracellularmatrix. This is a feature of many pathological conditions, such asrheumatoid and osteoarthritis, corneal, epidermal or gastric ulceration;tumor metastasis or invasion; periodontal disease and bone disease.Normally these catabolic enzymes are tightly regulated at the level oftheir synthesis as well as at their level of extracellular activitythrough the action of specific inhibitors, such asalpha-2-macroglobulins and TIMPs (tissue inhibitors of metalloprotease),which form inactive complexes with the MP's.

Osteo- and Rheumatoid Arthritis (OA and RA respectively) are destructivediseases of articular cartilage characterized by localized erosion ofthe cartilage surface. Findings have shown that articular cartilage fromthe femoral heads of patients with OA, for example, had a reducedincorporation of radiolabeled sulfate over controls, suggesting thatthere must be an enhanced rate of cartilage degradation in OA (Mankin etal. J. Bone Joint Surg. 52A, 1970, 424-434). There are four classes ofprotein degradative enzymes in mammalian cells: serine, cysteine,aspartic and metalloproteases. The available evidence supports that itis the metalloproteases which are responsible for the degradation of theextracellular matrix of articular cartilage in OA and RA. Increasedactivities of collagenases and stromelysin have been found in OAcartilage and the activity correlates with severity of the lesion(Mankin et al. Arthritis Rheum. 21, 1978, 761-766, Woessner et al.Arthritis Rheum. 26, 1983, 63-68 and Ibid. 27, 1984, 305-312). Inaddition, aggrecanase has been identified as providing the specificcleavage product of proteoglycan found in RA and OA patients (LohmanderL. S. et al. Arthritis Rheum. 36, 1993, 1214-22).

Therefore, metalloproteases (MP) have been implicated as the key enzymesin the destruction of mammalian cartilage and bone. It can be expectedthat the pathogenesis of such diseases can be modified in a beneficialmanner by the administration of MP inhibitors, and many compounds havebeen suggested for this purpose (see Wahl et al. Ann. Rep. Med. Chem.25, 175-184, AP, San Diego, 1990).

Tumor necrosis factor (TNF) is a cell-associated cytokine that isprocessed from a 26 kd precursor form to a 17 kd active form. TNF hasbeen shown to be a primary mediator in humans and in animals, ofinflammation, fever, and acute phase responses, similar to thoseobserved during acute infection and shock. Excess TNF has been shown tobe lethal. There is now considerable evidence that blocking the effectsof TNF with specific antibodies can be beneficial in a variety ofcircumstances including autoimmune diseases such as rheumatoid arthritis(Feldman et al, Lancet, 1994, 344, 1105) and non-insulin dependentdiabetes melitus. (Lohmander L. S. et al. Arthritis Rheum. 36, 1993,1214-22) and Crohn's disease (MacDonald T. et al. Clin. Exp. Immunol.81, 1990, 301).

Compounds which inhibit the production of TNF are therefore oftherapeutic importance for the treatment of inflammatory disorders.Recently, TNF-α converting enzyme (TACE), the enzyme responsible forTNF-α release from cells, were purified and sequenced (Black et alNature 1997, 385, 729; Moss et al Nature 1997, 385, 733). This inventiondescribes molecules that inhibit this enzyme and hence the secretion ofactive TNF-α from cells. These novel molecules provide a means ofmechanism based therapeutic intervention for diseases including but notrestricted to septic shock, haemodynamic shock, sepsis syndrome, postischemic reperfusion injury, malaria, Crohn's disease, inflammatorybowel diseases, mycobacterial infection, meningitis, psoriasis,congestive heart failure, fibrotic diseases, cachexia, graft rejection,cancer, diseases involving angiogenesis, autoimmune diseases, skininflammatory diseases, OA, RA, multiple sclerosis, radiation damage,hyperoxic alveolar injury, periodontal disease, HIV and non-insulindependent diabetes melitus.

Since excessive TNF production has been noted in several diseaseconditions also characterized by MMP-mediated tissue degradation,compounds which inhibit both MMPs and TNF production may also have aparticular advantage in diseases where both mechanisms are involved.

EP 0,780,286 describes MMP inhibitors of formula A:

wherein Y can be NHOH, R¹ and R² can combine to form a cycloalkyl orheterocyclo alkyl group, R³ and R⁴ can be a variety of groups includingH, and R⁵ can be substituted aryl.

WO 97/20824 depicts MMP inhibitors of formula B:

wherein ring V contains six atoms, Z is O or S, and Ar is an aryl orheteroaryl group. Ar is preferably a monocyclic aryl group with anoptional para substituent or an unsubstituted monocyclic heteroarylgroup.

EP 0,818,442 illustrates MMP inhibitors of formula C:

wherein Ar is optionally substituted phenyl or naphthyl, Z can be absentand X and Y can be a variety of substituents. Compounds of this sort arenot considered to be part of the present invention.

The compounds of the present invention act as inhibitors of MPs, inparticular TNF-α, MMPs, and/or aggrecanase. These novel molecules areprovided as anti-inflammatory compounds and cartilage protectingtherapeutics. The inhibition of aggrecanase, TNF-C, and othermetalloproteases by molecules of the present invention indicates theyare anti-inflammatory and should prevent the degradation of cartilage bythese enzymes, thereby alleviating the pathological conditions of OA andRA.

SUMMARY OF THE INVENTION

Accordingly, one object of the present invention is to provide novelcyclic hydroxamic acids useful as metalloprotease inhibitors orpharmaceutically acceptable salts or prodrugs thereof.

It is another object of the present invention to provide pharmaceuticalcompositions comprising a pharmaceutically acceptable carrier and atherapeutically effective amount of at least one of the compounds of thepresent invention or a pharmaceutically acceptable salt or prodrug formthereof.

It is another object of the present invention to provide a method fortreating inflammatory disorders, comprising: administering to a host, inneed of such treatment, a therapeutically effective amount of at leastone of the compounds of the present invention or a pharmaceuticallyacceptable salt or prodrug form thereof.

It is another object of the present invention to provide novel compoundsof the present invention for use in therapy.

It is another object of the present invention to provide the use ofnovel compounds of the present invention for the manufacture of amedicament for the treatment of a condition or disease mediated by MMPs,TNF, aggrecanase, or a combination thereof.

These and other objects, which will become apparent during the followingdetailed description, have been achieved by the inventors' discoverythat compounds of formula (I):

or pharmaceutically acceptable salt or prodrug forms thereof, wherein A,B, R¹, R², R^(2a), R^(2b), and R³ are defined below, are effectivemetalloprotease inhibitors.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

-   [1] Thus, in an embodiment, the present invention provides a novel    compound of formula I:    or a stereoisomer or pharmaceutically acceptable salt form thereof,    wherein;    -   A is selected from —COR⁵, —CO₂H, CH₂CO₂H, —CO₂R⁶, —CONHOH,        —CONHOR⁵, —CONHOR⁶, —N(OH)COR⁵, —N(OH)CHO, —SH, —CH₂SH,        —S(O)(═NH)R^(a), —SN₂H₂R^(a), —PO(OH)₂, and —PO(OH)NHR^(a);    -   ring B is a 3-13 membered non-aromatic carbocyclic or        heterocyclic ring comprising: carbon atoms, 0-3 carbonyl groups,        0-4 double bonds, and from 0-2 ring heteroatoms selected from O,        N, NR², and S(O)_(p), provided that ring B contains other than a        S—S, O—O, or S—O bond;    -   Z is absent or selected from a C₃₋₁₃ carbocycle substituted with        0-5 R^(b) and a 5-14 membered heterocycle comprising: carbon        atoms and 1-4 heteroatoms selected from the group consisting of        N, O, and S(O)_(p) and substituted with 0-5 R^(b);    -   U^(a) is absent or is selected from: O, NR^(a) ¹ , C(O), C(O)O,        OC(O), C(O)NR^(a) ¹ , NR^(a) ¹ C(O), OC(O)O, OC(O)NR^(a) ¹ ,        NR^(a) ¹ C(O)O, NR^(a) ¹ C(O)NR^(a) ¹ , S(O)_(p), S(O)_(p)NR^(a)        ¹ , NR^(a) ¹ S(O)_(p), and NR^(a) ¹ SO₂NR^(a) ¹ ;    -   X^(a) is absent or selected from C₁₋₁₀ alkylene, C₂₋₁₀        alkenylene, and C₂₋₁₀ alkynylene;    -   Y^(a) is absent or selected from O, NR^(a) ¹ , S(O)_(p), and        C(O);    -   Z^(a) is selected from H, a C₃₋₁₃ carbocycle substituted with        0-5 R^(c) and a 5-14 membered heterocycle comprising: carbon        atoms and 1-4 heteroatoms selected from the group consisting of        N, O, and S(O)_(p) and substituted with 0-5 R^(c);    -   provided that Z, U^(a), Y^(a), and Z^(a) do not combine to form        a N—N, N—O, O—N, O—O, S(O)_(p)—O, O—S(O)_(p) or        S(O)_(p)—S(O)_(p) group;    -   R¹ is selected from H, C₁₋₄ alkyl, phenyl, and benzyl;    -   R² is selected from Q, Cl, F, C₁₋₁₀ alkylene-Q substituted with        0-3 R^(b1), C₂₋₁₀ alkenylene-Q substituted with 0-3 R^(b1),        C₂₋₁₀ alkynylene-Q substituted with 0-3 R^(b1), (CR^(a)R^(a) ¹        )_(r) ₁ O(CR^(a)R^(a) ¹ )_(r)-Q, (CR^(a)R^(a) ¹ )_(r) ₁        NR^(a)(CR^(a)R^(a) ¹ ))_(r)-Q, (CR^(a)R^(a) ¹ )_(r) ₁        C(O)(CR^(a)R^(a) ¹ )_(r)-Q, (CR^(a)R^(a) ¹ )_(r) ₁        C(O)O(CR^(a)R^(a) ¹ )_(r)-Q, (CR^(a)R^(a) ¹ )_(r)C(O)O—C₂₋₅        alkenylene, (CR^(a)R^(a) ¹ )_(r) ₁ C(O)O—C₂₋₅ alkynylene,        (CR^(a)R^(a) ¹ )_(r) ₁ OC(O)(CR^(a)R^(a) ¹ )_(r)-Q, (CR^(a)R^(a)        ¹ )_(r) ₁ C(O)NR^(a)R^(a) ¹ , (CR^(a)R^(a) ¹ )_(r) ₁        C(O)NR^(a)(CR^(a)R^(a) ¹ )_(r)-Q, (CR^(a)R^(a) ¹ )_(r) ₁        NR^(a)C(O)(CR^(a)R^(a) ¹ )_(r)-Q, (CR^(a)R^(a) ¹ )_(r) ₁        OC(O)O(CR^(a)R^(a) ¹ )_(r)-Q, (CR^(a)R^(a) ¹ )_(r) ₁        OC(O)NR^(a)(CR^(a)R^(a) ¹ )_(r)-Q, (CR^(a)R^(a) ¹ )_(r) ₁        NR^(a)C(O)O(CR^(a)R^(a) ¹ )_(r)-Q, (CR^(a)R^(a) ¹ )_(r) ₁        NR^(a)C(O)NR^(a)(CR^(a)R^(a) ¹ )_(r)-Q, (CR^(a)R^(a) ¹ )_(r) ₁        S(O)_(p)(CR^(a)R^(a) ¹ )_(r)-Q, (CR^(a)R^(a) ¹ )_(r) ₁        SO₂NR^(a)(CR^(a)R^(a) ¹ )_(r)-Q, (CR^(a)R^(a) ¹ )_(r) ₁        NR^(a)SO₂(CR^(a)R^(a) ¹ )_(r)-Q, and (CR^(a)R^(a) ¹ )_(r) ₁        NR^(a)SO₂NR^(a)(CR^(a)R^(a) ¹ )_(r)-Q;    -   R^(2a) is selected from H, C₁₋₆ alkyl, OR^(a), NR^(a)R^(a) ¹ ,        and S(O)_(p)R^(a);    -   R^(2b) is H or C₁₋₆ alkyl;    -   Q is selected from H, a C₃₋₁₃ carbocycle substituted with 0-5        R^(d) and a 5-14 membered heterocycle comprising: carbon atoms        and 1-4 heteroatoms selected from the group consisting of N, O,        and S(O)_(p) and substituted with 0-5 R^(d);    -   R³ is selected from Q¹, Cl, F, C₁₋₆ alkylene-Q¹, C₂₋₆        alkenylene-Q¹, C₂₋₆ alkynylene-Q¹, (CR^(a)R^(a) ¹ )_(r) ₁        O(CR^(a)R^(a) ¹ )_(r)-Q¹, (CR^(a)R^(a) ¹ )_(r) ₁        NR^(a)(CR^(a)R^(a) ¹ )_(r)-Q¹, (CR^(a)R^(a) ¹ )_(r) ₁        NR^(a)C(O)(CR^(a)R^(a) ¹ )_(r)-Q¹, (CR^(a)R^(a) ¹ )_(r) ₁        C(O)NR^(a)(CR^(a)R^(a) ¹ )_(r)-Q¹, (CR^(a)R^(a) ¹ )_(r) ₁        C(O)(CR^(a)R^(a) ¹ )_(r)-Q¹, (CR^(a)R^(a) ¹ )_(r) ₁        C(O)O(CR^(a)R^(a) ¹ )_(r)-Q¹, (CR^(a)R^(a) ¹ ₂)_(r) ₁        S(O)_(p)(CR^(a)R^(a) ¹ )_(r)-Q¹, and (CR^(a)R^(a) ¹ )_(r) ₁        SO₂NR^(a)(CR^(a)R^(a) ¹ )_(r)-Q¹;    -   Q¹ is selected from H, phenyl substituted with 0-3 R^(d),        naphthyl substituted with 0-3 R^(d) and a 5-10 membered        heteroaryl comprising: carbon atoms and 1-4 heteroatoms selected        from the group consisting of N, O, and S(O)_(p) and substituted        with 0-3 R^(d);    -   R^(a), at each occurrence, is independently selected from H,        C₁₋₄ alkyl, phenyl and benzyl;    -   R^(a) ¹ , at each occurrence, is independently selected from H        and C₁₋₄ alkyl;    -   alternatively, R^(a)and R^(a) ¹ when attached to a nitrogen are        taken together with the nitrogen to which they are attached to        form a 5 or 6 membered ring comprising carbon atoms and from 0-1        additional heteroatoms selected from the group consisting of N,        O, and S(O)_(p);    -   R^(a) ² , at each occurrence, is independently selected from        C₁₋₄ alkyl, phenyl and benzyl;    -   R^(b), at each occurrence, is independently selected from C₁₋₆        alkyl, OR^(a), Cl, F, Br, I, ═O, —CN, NO₂, NR^(a)R^(a) ¹,        C(O)R^(a), C(O)OR^(a), C(O)NR^(a)R^(a) ¹ , R^(a)NC(O)NR^(a)R^(a)        ¹ , OC(O)NR^(a)R^(a) ¹ , R^(a)NC(O)O, S(O)₂NR^(a)R^(a) ¹ ,        NR^(a)S(O)₂R^(a) ² , NR^(a)S(O)₂NR^(a)R^(a) ¹ ,        OS(O)₂NR^(a)R^(a) ¹ , NR^(a)S(O)₂R^(a) ² , S(O)_(p)R^(a) ² ,        CF₃, and CF₂CF₃;    -   R^(b) ¹ , at each occurrence, is independently selected from        OR^(a), Cl, F, Br, I, ═O, —CN, NLO₂, and NR^(a)R^(a) ¹ ;    -   R^(c), at each occurrence, is independently selected from C₁₋₆        alkyl, OR^(a), Cl, F, Br, I, ═O, —CN, NO₂, NR^(a) ¹a ¹ ,        C(O)R^(a), C(O)OR^(a), C(O)NR^(a)R^(a) ¹ , R^(a)NC(O)NR^(a)R^(a)        ¹ , OC(O)NR^(a)R^(a) ¹ , R^(a)NC(O)O, S(O)₂NR^(a)R^(a) ¹ ,        NR^(a)S(O)₂R^(a) ² , NR^(a)S(O)₂NR^(a)R^(a) ¹ ,        OS(O)₂NR^(a)R^(a) ¹ , NR^(a)S(O)₂R^(a) ² , S(O)_(p)R^(a) ² ,        CF₃, CF₂CF₃, C₃₋₁₀ carbocycle substituted with 0-3 R^(c1) and a        5-14 membered heterocycle comprising: carbon atoms and 1-4        heteroatoms selected from the group consisting of N, O, and        S(O)_(p) and substituted with 0-3 R^(c1);    -   R^(c1), at each occurrence, is independently selected from C₁₋₆        alkyl, OR^(a), Cl, F, Br, I, ═O, —CN, NO₂, NR^(a)R^(a) ¹a ¹ ,        C(O)R^(a), C(O)OR^(a), C(O)NR^(a)R^(a) ¹ , R^(a)NC(O)NR^(a)R^(a)        ¹ , OC(O)NR^(a)R^(a) ¹ , R^(a)NC(O)O, S(O)₂NR^(a)R^(a) ¹ ,        NR^(a)S(O)₂R^(a) ² , NR^(a)S(O)₂NR^(a)R^(a) ¹ ,        OS(O)₂NR^(a)R^(a) ¹ , NR^(a)S(O)₂R^(a) ² , S(O)_(p)R^(a) ² ,        CF₃, and CF₂CF₃;    -   R^(d), at each occurrence, is independently selected from C₁₋₆        alkyl, OR^(a), Cl, F, Br, I, ═O, —CN, NO₂, NR^(a)R¹a ¹ ,        C(O)R^(a), C(O)OR^(a), C(O)NR^(a)R^(a) ¹ , R^(a)NC(O)NR^(a)R^(a)        ¹ , OC(O)NR^(a)R^(a) ¹ , R^(a)NC(O)O, S(O)₂NR^(a)R^(a) ¹ ,        NR^(a)S(O)₂R^(a) ² , NR^(a)S(O)₂NR^(a)R^(a) ¹ ,        OS(O)₂NR^(a)R^(a) ¹ , NR^(a)S(O)₂R^(a) ² , S(O)_(p)R^(a) ² ,        CF₃, CF₂CF₃, C₃₋₁₀ carbocycle and a 5-14 membered heterocycle        comprising: carbon atoms and 1-4 heteroatoms selected from the        group consisting of N, O, and S(O)_(p);    -   R⁵, at each occurrence, is selected from C₁₋₁₀ alkyl substituted        with 0-2 R^(b), and C₁₋₈ alkyl substituted with 0-2 R^(e);    -   R^(e), at each occurrence, is selected from phenyl substituted        with 0-2 R^(b) and biphenyl substituted with 0-2 R^(b);    -   R⁶, at each occurrence, is selected from phenyl, naphthyl, C₁₋₁₀        alkyl-phenyl-C₁₋₆ alkyl-, C₃₋₁₁ cycloalkyl, C₁₋₆        alkylcarbonyloxy-C₁₋₃ alkyl-, C₁₋₆ alkoxycarbonyloxy-C₁₋₃        alkyl-, C₂₋₁₀ alkoxycarbonyl, C₃₋₆ cycloalkylcarbonyloxy-C₁₋₃        alkyl-, C₃₋₆ cycloalkoxycarbonyloxy-C₁₋₃ alkyl-, C₃₋₆        cycloalkoxycarbonyl, phenoxycarbonyl, phenyloxycarbonyloxy-C₁₋₃        alkyl-, phenylcarbonyloxy-C₁₋₃ alkyl-, C₁₋₆ alkoxy-C₁₋₆        alkylcarbonyloxy-C₁₋₃ alkyl-, [5-(C₁-C₅        alkyl)-1,3-dioxa-cyclopenten-2-one-yl]methyl,        [5-(R^(a))-1,3-dioxa-cyclopenten-2-one-yl]methyl,        (5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyl, —C₁₋₁₀        alkyl-NR⁷R^(7a), —CH(R⁸)OC(═O)R⁹, and —CH(R⁸)OC(═O)OR⁹;    -   R⁷ is selected from H and C₁₋₁₀ alkyl, C₂₋₆ alkenyl, C₃₋₆        cycloalkyl-C₁₋₃ alkyl-, and phenyl-C₁₋₆ alkyl-;    -   R^(7a) is selected from H and C₁₋₁₀ alkyl, C₂₋₆ alkenyl, C₃₋₆        cycloalkyl-C₁₋₃ alkyl-, and phenyl-C₁₋₆ alkyl-;    -   R⁸ is selected from H and C₁₋₄ linear alkyl;    -   R⁹ is selected from H, C₁₋₈ alkyl substituted with 1-2 R^(f),        C₃₋₈ cycloalkyl substituted with 1-2 R^(f), and phenyl        substituted with 0-2 R^(b);    -   R^(f), at each occurrence, is selected from C₁₋₄ alkyl, C₃₋₈        cycloalkyl, C₁₋₅ alkoxy, and phenyl substituted with 0-2 R^(b);    -   p, at each occurrence, is selected from 0, 1, and 2;    -   r, at each occurrence, is selected from 0, 1, 2, 3, and 4; and,    -   r¹, at each occurrence, is selected from 0, 1, 2, 3, and 4.-   [2] In a preferred embodiment, the present invention provides a    novel compound of formula II:    or a stereoisomer or pharmaceutically acceptable salt form thereof,    wherein;    -   A is selected from —CO₂H, CH₂CO₂H, —CONHOH, —CONHOR⁵, —CONHOR⁶,        —N(OH)COR⁵, —N(OH)CHO, —SH, and —CH₂SH;    -   ring B is a 4-7 membered non-aromatic carbocyclic or        heterocyclic ring comprising: carbon atoms, 0-1 carbonyl groups,        0-1 double bonds, and from 0-2 ring heteroatoms selected from O,        N, and NR², provided that ring B contains other than a O—O bond;    -   Z is absent or selected from a C₃₋₁₁ carbocycle substituted with        0-4 R^(b) and a 5-11 membered heterocycle comprising: carbon        atoms and 1-4 heteroatoms selected from the group consisting of        N, O, and S(O)_(p) and substituted with 0-3 R^(b);    -   U^(a) is absent or is selected from: O, NR^(a) ¹ , C(O), C(O)O,        C(O)NR^(a) ¹ , NR^(a) ¹ C(O), S(O)_(p), and S(O)_(p)NR^(a) ¹ ;    -   X^(a) is absent or selected from C₁₋₄ alkylene, C₂₋₄ alkenylene,        and C₂₋₄ alkynylene;    -   Y^(a) is absent or selected from O and NR^(a) ¹ ;    -   Z^(a) is selected from H, a C₃₋₁₀ carbocycle substituted with        0-5 R^(c) and a 5-10 membered heterocycle comprising: carbon        atoms and 1-4 heteroatoms selected from the group consisting of        N, O, and S(O)_(p) and substituted with 0-5 R^(c);    -   provided that Z, U^(a), Y^(a), and Z^(a) do not combine to form        a N—N, N—O, O—N, O—O, S(O)_(p)—O, O—S(O)_(p) or        S(O)_(p)—S(O)_(p) group;    -   R¹ is selected from H, C₁₋₄ alkyl, phenyl, and benzyl;    -   R² is selected from Q, C₁₋₆ alkylene-Q, C₂₋₆ alkenylene-Q, C₂₋₆        alkynylene-Q, (CR^(a)R^(a) ¹ )_(r) ₁ O(CR^(a)R^(a) ¹ )_(r)-Q,        (CR^(a)R^(a) ¹ )_(r) ₁ NR^(a)(CR^(a)R^(a) ¹ )_(r)-Q,        (CR^(a)R^(a) ¹ )_(r) ₁ C(O)(CR^(a)R^(a) ¹ )_(r)-Q, (CR^(a)R^(a)        ¹ )_(r) ₁ C(O)O(CR^(a)R^(a) ¹ )_(r)-Q, (CR^(a)R^(a) ¹        )_(r)C(O)NR^(a)R^(a) ¹ , (CR^(a)R^(a) ¹ )_(r) ₁        C(O)NR^(a)(CR^(a)R^(a) ¹ )_(r)-Q, (CR^(a)R^(a) ¹ )_(r) ₁        S(O)_(p)(CR^(a)R^(a) ¹ )_(r)-Q, and (CR^(a)R^(a) ¹ )_(r) ₁        SO₂NR^(a)(CR^(a)R^(a) ¹ )_(r)-Q;    -   Q is selected from H, a C₃₋₆ carbocycle substituted with 0-5        R^(d), and a 5-10 membered heterocycle comprising: carbon atoms        and 1-4 heteroatoms selected from the group consisting of N, O,        and S(O)_(p) and substituted with 0-5 R^(d);    -   R^(a), at each occurrence, is independently selected from H,        C₁₋₄ alkyl, phenyl and benzyl;    -   R^(a) ¹ , at each occurrence, is independently selected from H        and C₁₋₄ alkyl;    -   alternatively, R^(a) and R^(a) ¹ when attached to a nitrogen are        taken together with the nitrogen to which they are attached to        form a 5 or 6 membered ring comprising carbon atoms and from 0-1        additional heteroatoms selected from the group consisting of N,        O, and S(O)_(p);    -   R^(a) ² , at each occurrence, is independently selected from        C₁₋₄ alkyl, phenyl and benzyl;    -   R^(b), at each occurrence, is independently selected from C₁₋₆        alkyl, OR^(a), Cl, F, Br, ═O, —CN, NR^(a)R^(a) ¹ , C(O)R^(a),        C(O)OR^(a), C(O)NR^(a)R^(a) ¹ , S(O)₂NR^(a)R^(a) ¹ ,        S(O)_(p)R^(a) ² , and CF₃;    -   R^(c), at each occurrence, is independently selected from C₁₋₆        alkyl, OR^(a), Cl, F, Br, ═O, —CN, NR^(a)R^(a) ¹ , C(O)R^(a),        C(O)OR^(a), C(O)NR^(a)R^(a) ¹ , S(O)₂NR^(a)R^(a) ¹ ,        S(O)_(p)R^(a) ² , CF₃, C₃₋₆ carbocycle and a 5-6 membered        heterocycle comprising: carbon atoms and 1-4 heteroatoms        selected from the group consisting of N, O, and S(O)_(p);    -   R_(d), at each occurrence, is independently selected from C₁₋₆        alkyl, OR^(a), Cl, F, Br, ═O, —CN, NR^(a)R^(a) ¹ , C(O)R^(a),        C(O)OR^(a), C(O)NR^(a)R^(a) ¹ , S(O)₂NR^(a)R^(a) ¹ ,        S(O)_(p)R^(a) ² , CF₃, C₃₋₆ carbocycle and a 5-6 membered        heterocycle comprising: carbon atoms and 1-4 heteroatoms        selected from the group consisting of N, O, and S(O)_(p);    -   R⁵, at each occurrence, is selected from C₁₋₆ alkyl substituted        with 0-2 R^(b), and C₁₋₄ alkyl substituted with 0-2 R^(e);    -   R^(e), at each occurrence, is selected from phenyl substituted        with 0-2 R^(b) and biphenyl substituted with 0-2 R^(b);    -   R⁶, at each occurrence, is selected from phenyl, naphthyl, C₁₋₁₀        alkyl-phenyl-C₁₋₆ alkyl-, C₃₋₁₁ cycloalkyl, C₁₋₆        alkylcarbonyloxy-C₁₋₃ alkyl-, C₁₋₆ alkoxycarbonyloxy-C₁₋₃        alkyl-, C₂₋₁₀ alkoxycarbonyl, C₃₋₆ cycloalkylcarbonyloxy-C₁₋₃        alkyl-, C₃₋₆ cycloalkoxycarbonyloxy-C₁₋₃ alkyl-, C₃₋₆        cycloalkoxycarbonyl, phenoxycarbonyl, phenyloxycarbonyloxy-C₁₋₃        alkyl-, phenylcarbonyloxy-C₁₋₃ alkyl-, C₁₋₆ alkoxy-C₁₋₆        alkylcarbonyloxy-C₁₋₃ alkyl-, [5-(C₁-C₅        alkyl)-1,3-dioxa-cyclopenten-2-one-yl]methyl,        [5-(R^(a))-1,3-dioxa-cyclopenten-2-one-yl]methyl,        (5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyl, —C₁₋₁₀        alkyl-NR⁷R^(7a), —CH(R⁸)OC(═O)R⁹, and —CH(R⁸)OC(═O)OR⁹;    -   R⁷ is selected from H and C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₆        cycloalkyl-C₁₋₃ alkyl-, and phenyl-C₁₋₆ alkyl-;    -   R^(7a) is selected from H and C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₆        cycloalkyl-C₁₋₃ alkyl-, and phenyl-C₁₋₆ alkyl-;    -   R⁸ is selected from H and C₁₋₄ linear alkyl;    -   R⁹ is selected from H, C₁₋₆ alkyl substituted with 1-2 R^(f),        C₃₋₆ cycloalkyl substituted with 1-2 R^(f), and phenyl        substituted with 0-2 R^(b);    -   R^(f), at each occurrence, is selected from C₁₋₄ alkyl, C₃₋₆        cycloalkyl, C₁₋₅ alkoxy, and phenyl substituted with 0-2 R^(b);    -   p, at each occurrence, is selected from 0, 1, and 2;    -   r, at each occurrence, is selected from 0, 1, 2, 3, and 4; and,    -   r¹, at each occurrence, is selected from 0, 1, 2, 3, and 4.-   [3] In a more preferred embodiment, the present invention provides a    novel compound of formula IIIa or IIIb:    or a stereoisomer or pharmaceutically acceptable salt form thereof,    wherein;    -   A is selected from —CO₂H, CH₂CO₂H, —CONHOH, —CONHOR⁵, —N(OH)CHO,        and —N(OH)COR⁵;    -   Z is absent or selected from a C₅₋₆ carbocycle substituted with        0-3 R^(b) and a 5-6 membered heteroaryl comprising carbon atoms        and from 1-4 heteroatoms selected from the group consisting of        N, O, and S(O)_(p) and substituted with 0-3 R^(b);    -   U^(a) is absent or is selected from: O, NR^(a) ¹ , C(O),        C(O)NR^(a) ¹ , S(O)_(p), and S(O)_(p)NR^(a) ¹ ;    -   X^(a) is absent or selected from C₁₋₄ alkylene, C₂₋₄ alkenylene,        and C₂₋₄ alkynylene    -   Y^(a) is absent or selected from O and NR^(a) ¹ ;    -   Z^(a) is selected from H, a C₅₋₆ carbocycle substituted with 0-3        R^(c) and a 5-10 membered heteroaryl comprising carbon atoms and        from 1-4 heteroatoms selected from the group consisting of N, O,        and S(O)_(p) and substituted with 0-3 R^(c);    -   provided that Z, U^(a), Y^(a), and Z^(a) do not combine to form        a N—N, N—O, O—N, O—O, S(O)_(p)—O, O—S(O)_(p) or        S(O)_(p)—S(O)_(p) group;    -   R¹ is selected from H C₁₋₄ alkyl, phenyl, and benzyl;    -   R² is selected from Q, C₁₋₆ alkylene-Q, C₂₋₆ alkenylene-Q, C₂₋₆        alkynylene-Q, (CR^(a)R^(a) ¹ )_(r) ₁ C(O)(CR^(a)R^(a) ¹ )_(r)-Q,        (CR^(a)R^(a) ¹ )_(r) ₁ C(O)O(CR^(a)R^(a) ¹ )_(r)-Q, (CR^(a)R^(a)        ² )_(r) ₁ C(O)NR^(a)R^(a) ¹ , (CR^(a)R^(a) ² )_(r) ₁        C(O)NR^(a)(CR^(a)R^(a) ¹ )_(r)-Q, and (CR^(a)R^(a) ¹ )_(r) ₁        S(O)_(p)(CR^(a)R^(a) ¹ )_(r)-Q;    -   Q is selected from H, a C₃₋₆ carbocycle substituted with 0-3        R^(d) and a 5-10 membered heterocycle comprising: carbon atoms        and 1-4 heteroatoms selected from the group consisting of N, O,        and S(O)_(p) and substituted with 0-3 R^(d);    -   R^(a), at each occurrence, is independently selected from H,        C₁₋₄ alkyl, phenyl and benzyl;    -   R^(a1), at each occurrence, is independently selected from H and        C₁₋₄ alkyl;    -   R^(a) ² , at each occurrence, is independently selected from        C₁₋₄ alkyl, phenyl, and benzyl;    -   R_(b), at each occurrence, is independently selected from C₁₋₄        alkyl, OR^(a), Cl, F, ═O, NR^(a)R^(a) ¹ , C(O)R^(a), C(O)OR^(a),        C(O)NR^(a)R^(a) ¹ , S(O)₂NR^(a)R^(a) ¹ , S(O)_(p)R^(a) ² , and        CF₃;    -   R^(c), at each occurrence, is independently selected from C₁₋₆        alkyl, OR^(a), Cl, F, Br, ═O, NR^(a)R^(a) ¹ , C(O)R^(a),        C(O)NR^(a)R^(a) ¹ , S(O)₂NR^(a)R^(a) ¹ , S(O)_(p)R^(a) ² , and        CF₃;    -   R^(d), at each occurrence, is independently selected from C₁₋₆        alkyl, OR^(a), Cl, F, Br, ═O, NR^(a)R^(a) ¹ , C(O)R^(a),        C(O)NR^(a)R^(a) ¹ , S(O)₂NR^(a)R^(a) ¹ , S(O)_(p)R^(a) ² , CF₃,        and phenyl;    -   R⁵, at each occurrence, is selected from C₁₋₄ alkyl substituted        with 0-2 R^(b), and C₁₋₄ alkyl substituted with 0-2 R^(e);    -   R^(e), at each occurrence, is selected from phenyl substituted        with 0-2 R^(b) and biphenyl substituted with 0-2 R^(b);    -   p, at each occurrence, is selected from 0, 1, and 2;    -   r, at each occurrence, is selected from 0, 1, 2, 3, and 4;    -   r¹, at each occurrence, is selected from 0, 1, 2, 3, and 4; and,    -   s and s¹ combine to total 2, 3, or 4.-   [4] In a further preferred embodiment, the present invention    provides a novel compound of formula IVa or IVb:    or a stereoisomer or pharmaceutically acceptable salt form thereof,    wherein;    -   Z is absent or selected from phenyl substituted with 0-3 R^(b)        and pyridyl substituted with 0-3 R^(b);    -   U^(a) is absent or is O;    -   X^(a) is absent or is CH₂ or CH₂CH₂;    -   Y^(a) is absent or is O;    -   Z^(a) is selected from H, phenyl substituted with 0-3 R^(c),        pyridyl substituted with 0-3 R^(c), and quinolinyl substituted        with 0-3 R^(c);    -   provided that Z, U^(a), Y^(a), and Z^(a) do not combine to form        a N—N, N—O, O—N, or O—O group;    -   R¹ is selected from H, CH₃, and CH₂CH₃;    -   R² is selected from Q, C₁₋₆ alkylene-Q, C₂₋₆ alkynylene-Q,        C(O)(CR^(a)R^(a) ¹ )_(r)-Q, C(O)O(CR^(a)R^(a) ¹ )_(r)-Q,        C(O)NR^(a)(CR^(a)R^(a) ¹ )_(r)-Q, and S(O)_(p)(CR^(a)R^(a) ¹        )_(r)-Q;    -   Q is selected from H, cyclopropyl substituted with 0-1 R^(d),        cyclobutyl substituted with 0-1 R^(d), cyclopentyl substituted        with 0-1 R^(d), cyclohexyl substituted with 0-1 R^(d), phenyl        substituted with 0-2 R^(d) and a heteroaryl substituted with 0-3        R^(d), wherein the heteroaryl is selected from pyridyl,        quinolinyl, thiazolyl, furanyl, imidazolyl, and isoxazolyl;    -   R^(a), at each occurrence, is independently selected from H,        CH₃, and CH₂CH₃;    -   R^(a) ¹ , at each occurrence, is independently selected from H,        CH₃, and CH₂CH₃;    -   R^(a) ² , at each occurrence, is independently selected from H,        CH₃, and CH₂CH₃;    -   R^(b), at each occurrence, is independently selected from C₁₋₄        alkyl, OR^(a), Cl, F, ═O, NR^(a)R^(a) ¹ , C(O)R^(a), C(O)OR^(a),        C(O)NR^(a)R^(a) ¹ , S(O)₂NR^(a)R^(a) ¹ , S(O)_(p)R^(a) ² , and        CF₃;    -   R^(c), at each occurrence, is independently selected from C₁₋₆        alkyl, OR^(a), Cl, F, Br, ═O, NR^(a)R^(a) ¹ , C(O)R^(a),        C(O)NR^(a)R^(a) ¹ , S(O)₂NR^(a)R^(a) ¹ , S(O)_(p)R^(a) ² , and        CF₃;    -   R^(d), at each occurrence, is independently selected from C₁₋₆        alkyl, OR^(a), Cl, F, Br, ═O, NR^(a)R^(a) ¹ , C(O)R^(a),        C(O)NR^(a)R^(a) ¹ , S(O)₂NR^(a)R^(a) ¹ , S(O)_(p)R^(a) ² , CF₃        and phenyl;    -   p, at each occurrence, is selected from 0, 1, and 2;    -   r, at each occurrence, is selected from 0, 1, 2, and 3;    -   r¹, at each occurrence, is selected from 0, 1, 2, and 3; and,    -   s and s¹ combine to total 2, 3, or 4.-   [5] In another more preferred embodiment, the present invention    provides a novel compound of formula II, wherein;    -   A is selected from —CO₂H, CH₂CO₂H, —CONHOH, —CONHOR⁵, —N(OH)CHO,        and —N(OH)COR⁵;    -   ring B is a 4-7 membered non-aromatic carbocyclic or        heterocyclic ring comprising: carbon atoms, 0-1 carbonyl groups,        0-1 double bonds, and from 0-2 ring heteroatoms selected from O,        N, and NR², provided that ring B contains other than a O—O bond;    -   Z is absent or selected from a C₅₋₆ carbocycle substituted with        0-3 R^(b) and a 5-6 membered heteroaryl comprising carbon atoms        and from 1-4 heteroatoms selected from the group consisting of        N, O, and S(O)_(p) and substituted with 0-3 R^(b);    -   U^(a) is absent or is selected from: O, NR^(a) ¹ , C(O),        C(O)NR^(a) ¹ , S(O)_(p), and S(O)_(p)NR^(a) ¹ ;    -   X^(a) is absent or selected from C₁₋₂ alkylene, C₂₋₄ alkenylene,        and C₂₋₄ alkynylene    -   Y^(a) is absent or selected from O and NR^(a) ¹ ;    -   Z^(a) is selected from H, a C₅₋₆ carbocycle substituted with 0-3        R^(c) and a 5-10 membered heteroaryl comprising carbon atoms and        from 1-4 heteroatoms selected from the group consisting of N, O,        and S(O)_(p) and substituted with 0-3 R^(c);    -   provided that Z, U^(a), Y^(a), and Z^(a) do not combine to form        a N—N, N—O, O—N, O—O, S(O)_(p)—O, O—S(O)_(p) or        S(O)_(p)—S(O)_(p) group;    -   R¹ is selected from H, C₁₋₄ alkyl, phenyl, and benzyl;    -   R² is (CR^(a)R^(a) ¹ )_(r) ₁ O(CR^(a)R^(a) ¹ )_(r)-Q or        (CR^(a)R^(a) ¹ )_(r) ₁ NR^(a)(CR^(a)R^(a) ¹ )_(r)-Q;    -   Q is selected from H, a C₃₋₆ carbocycle substituted with 0-3        R^(d) and a 5-10 membered heterocycle comprising: carbon atoms        and 1-4 heteroatoms selected from the group consisting of N, O,        and S(O)_(p) and substituted with 0-3 R^(d);    -   R^(a), at each occurrence, is independently selected from H,        C₁₋₄ alkyl, phenyl and benzyl;    -   R^(a) ¹ , at each occurrence, is independently selected from H        and C₁₋₄ alkyl;    -   R^(a) ² , at each occurrence, is independently selected from        C₁₋₄ alkyl, phenyl and benzyl;    -   R^(b), at each occurrence, is independently selected from C₁₋₄        alkyl, OR^(a), Cl, F, ═O, NR^(a)R^(a) ¹ , C(O)R^(a), C(O)OR^(a),        C(O)NR^(a)R^(a) ¹ , S(O)₂NR^(a)R^(a) ¹ , S(O)_(p)R^(a) ² , and        CF₃;    -   R^(c), at each occurrence, is independently selected from C₁₋₆        alkyl, OR^(a), Cl, F, Br, ═O, NR^(a)R^(a) ¹ , C(O)R^(a),        C(O)NR^(a)R^(a) ¹ , S(O)₂NR^(a)R^(a) ¹ , S(O)_(p)R^(a) ² , and        CF₃;    -   R^(d), at each occurrence, is independently selected from C₁₋₆        alkyl, OR^(a), Cl, F, Br, ═O, NR^(a)R^(a) ¹ , C(O)R^(a),        C(O)NR^(a)R^(a) ¹ , S(O)₂NR^(a)R^(a) ¹ , S(O)_(p)R^(a) ² , CF₃        and phenyl;    -   R⁵, at each occurrence, is selected from C₁₋₄ alkyl substituted        with 0-2 R^(b), and C₁₋₄ alkyl substituted with 0-2 R^(e);    -   R^(e), at each occurrence, is selected from phenyl substituted        with 0-2 R^(b) and biphenyl substituted with 0-2 R^(b);    -   p, at each occurrence, is selected from 0, 1, and 2;    -   r, at each occurrence, is selected from 0, 1, 2, 3, and 4; and,    -   r¹, at each occurrence, is selected from 0, 1, 2, 3, and 4.-   [6] In another further preferred embodiment, the present invention    provides a novel compound of formula II, wherein;    -   A is —CONHOH;    -   ring B is a 5-6 membered non-aromatic carbocyclic or        heterocyclic ring comprising: carbon atoms, 0-1 carbonyl groups,        0-1 double bonds, and from 0-2 ring heteroatoms selected from O,        N, and NR², provided that ring B contains other than a O—O bond;    -   Z is absent or selected from phenyl substituted with 0-3 R^(b)        and pyridyl substituted with 0-3 R^(b);    -   U^(a) is absent or is O;    -   X^(a) is absent or is CH₂ or CH₂CH₂;    -   Y^(a) is absent or is O;    -   Z^(a) is selected from H, phenyl substituted with 0-3 R^(c),        pyridyl substituted with 0-3 R^(c), and quinolinyl substituted        with 0-3 R^(c);    -   provided that Z, U^(a), Y^(a), and Z^(a) do not combine to form        a N—N, N—O, O—N, or O—O group;    -   R¹ is selected from H, CH₃, and CH₂CH₃;    -   R² is (CR^(a)R^(a) ¹ )_(r) ₁ O(CR^(a)R^(a) ¹ )_(r)-Q or        (CR^(a)R^(a) ¹ )_(r) ₁ NR^(a)(CR^(a)R^(a) ¹ )_(r)-Q;    -   Q is selected from H, cyclopropyl substituted with 0-1 R^(d),        cyclobutyl substituted with 0-1 R^(d), cyclopentyl substituted        with 0-1 R^(d), cyclohexyl substituted with 0-1 R^(d), phenyl        substituted with 0-2 R^(d), and a heteroaryl substituted with        0-3 R^(d), wherein the heteroaryl is selected from pyridyl,        quinolinyl, thiazolyl, furanyl, imidazolyl, and isoxazolyl;    -   R^(a), at each occurrence, is independently selected from H,        CH₃, and CH₂CH₃;    -   R^(a) ¹ , at each occurrence, is independently selected from H,        CH₃, and CH₂CH₃;    -   R^(a) ² , at each occurrence, is independently selected from H,        CH₃, and CH₂CH₃;    -   R^(b), at each occurrence, is independently selected from C₁₋₄        alkyl, OR^(a), Cl, F, ═O, NR^(a)R^(a) ¹ , C(O)R^(a), C(O)OR^(a),        C(O)NR^(a)R^(a) ¹ , S(O)₂NR^(a)R^(a) ¹ , S(O)_(p)R^(a) ² , and        CF₃;    -   R^(c), at each occurrence, is independently selected from C₁₋₆        alkyl, OR^(a), Cl, F, Br, ═O, NR^(a)R^(a) ¹ , C(O)R^(a),        C(O)NR^(a)R^(a) ¹ , S(O)₂NR^(a)R^(a) ¹ , S(O)_(p)R^(a) ² , and        CF₃;    -   R^(d), at each occurrence, is independently selected from C₁₋₆        alkyl, OR^(a), Cl, F, Br, ═O, NR^(a)R^(a) ¹ , C(O)R^(a),        C(O)NR^(a)R^(a) ¹ , S(O)₂NR^(a)R^(a) ¹ , S(O)_(p)R^(a) ² , CF₃        and phenyl;    -   p, at each occurrence, is selected from 0, 1, and 2;    -   r, at each occurrence, is selected from 0, 1, 2, and 3; and,    -   r¹, at each occurrence, is selected from 0, 1, 2, and 3.-   [7] In another preferred embodiment, the present invention provides    a compound selected from the group:    -   N-{(1R,2S)-2-[(hydroxyamino)carbonyl]cyclopentyl}-2′-(trifluoromethyl)[1,1′-biphenyl]-4-carboxamide    -   N-{(1R,2S)-2-[(hydroxyamino)carbonyl]cyclopentyl}-4-[2-(trifluoromethyl)phenoxy]benzamide    -   N-{(1R,2S)-2-[(hydroxyamino)carbonyl]cyclopentyl}-4-(3-methyl-2-pyridinyl)benzamide    -   N-{(1R,2S)-2-[(hydroxyamino)carbonyl]cyclopentyl}[1,1′-biphenyl]-4-carboxamide    -   N-{(1R,2S)-2-[(hydroxyamino)carbonyl]cyclopentyl}-4-phenoxybenzamide    -   4-(benzyloxy)-N-{(1R,2S)-2-[(hydroxyamino)carbonyl]cyclopentyl}benzamide    -   N-{(1R,2S)-2-[(hydroxyamino)carbonyl]cyclopentyl}-2′-methoxy[1,1′-biphenyl]-4-carboxamide    -   N-{(1R,2S)-2-[(hydroxyamino)carbonyl]cyclopentyl}-2′-methyl[1,1′-biphenyl]-4-carboxamide    -   N-{(1R,2S)-2-[(hydroxyamino)carbonyl]cyclopentyl}-4-(2-methoxyphenoxy)benzamide    -   N-{(1R,2S)-2-[(hydroxyamino)carbonyl]cyclopentyl}-4-(2-methylphenoxy)benzamide    -   N-{(1R,2S)-2-[(hydroxyamino)carbonyl]cyclopentyl}-4-(3-methylphenoxy)benzamide    -   4-(5,8-dihydro-4-quinolinyl)-N-{(1R,2S)-2-[(hydroxyamino)carbonyl]cyclopentyl}benzamide    -   N-{(1R,2S)-2-[(hydroxyamino)carbonyl]cyclopentyl}-3′,5′-dimethyl[1,1′-biphenyl]-4-carboxamide    -   N-{(1R,2S)-2-[(hydroxyamino)carbonyl]cyclopentyl}-6-(2-methylphenyl)nicotinamide    -   N-{(1R,2S)-2-[(hydroxyamino)carbonyl]cyclopentyl}-6-(2-methoxyphenyl)nicotinamide    -   (3S,4S)-N-hydroxy-1-isopropyl-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-3-pyrrolidinecarboxamide    -   (3S,4S)-1-(2,2-dimethylpropanoyl)-N-hydroxy-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-3-pyrrolidinecarboxamide    -   (3S,4S)-N-hydroxy-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-1-(methylsulfonyl)-3-pyrrolidinecarboxamide    -   (3S,4S)-N-hydroxy-1-methyl-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-3-pyrrolidinecarboxamide    -   tert-butyl        (3S,4S)-3-[(hydroxyamino)carbonyl]-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-1-pyrrolidinecarboxylate    -   (3S,4S)-N-hydroxy-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-3-pyrrolidinecarboxamide    -   tert-butyl        4-[cis-3-[(hydroxyamino)carbonyl]-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)pyrrolidinyl]-1-piperidinecarboxylate    -   cis-N-hydroxy-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-1-(4-piperidinyl)-3-pyrrolidinecarboxamide    -   cis-1-[3-[(1,1-dimethylethoxy)carbonyl]pyrollidinyl]-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-pyrollidinecarboxamide    -   cis-N-hydroxy-1-[3-pyrollidinyl]-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-pyrollidinecarboxamide    -   tert-butyl        (3R,4R)-3-[(hydroxyamino)carbonyl]-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-1-pyrrolidinecarboxylate    -   tert-butyl        (3S,4R)-3-[(hydroxyamino)carbonyl]-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-1-pyrrolidinecarboxylate    -   (3S,4R)-N-hydroxy-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-3-pyrrolidinecarboxamide    -   tert-butyl        (3R,4S)-3-[(hydroxyamino)carbonyl]-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-1-pyrrolidinecarboxylate    -   (3R,4S)-N-hydroxy-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-3-pyrrolidinecarboxamide    -   N-{(1R,2S)-2-[(hydroxyamino)carbonyl]cyclopentyl}-4-(4-pyridinyl)benzamide    -   (3S,4S)-1-(1,1-dimethyl-2-propynyl)-N-hydroxy-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-3-pyrrolidinecarboxamide    -   (3S,4S)-N-hydroxy-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-1-(2-propynyl)-3-pyrrolidinecarboxamide    -   (3S,4S)-1-allyl-N-hydroxy-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-3-pyrrolidinecarboxamide    -   (3S,4S)-N-hydroxy-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-1-propyl-3-pyrrolidinecarboxamide    -   (3S,4S)-N-hydroxy-1-(2-methyl-2-propenyl)-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-3-pyrrolidinecarboxamide    -   (3S,4S)-1-(1,1-dimethyl-2-propenyl)-N-hydroxy-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-3-pyrrolidinecarboxamide    -   (3S,4S)-N-hydroxy-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-1-tert-pentyl-3-pyrrolidinecarboxamide    -   (3S,4S)-N-hydroxy-1-isopentyl-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-3-pyrrolidinecarboxamide    -   (3S,4S)-N-hydroxy-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-1-neopentyl-3-pyrrolidinecarboxamide    -   (3S,4S)-1-butyl-N-hydroxy-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-3-pyrrolidinecarboxamide    -   (3S,4S)-1-(3-butenyl)-N-hydroxy-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-3-pyrrolidinecarboxamide    -   (3S,4S)-1-(2-butynyl)-N-hydroxy-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-3-pyrrolidinecarboxamide    -   (3S,4S)-1-(2-furylmethyl)-N-hydroxy-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-3-pyrrolidinecarboxamide    -   (3S,4S)-N-hydroxy-1-[(5-methyl-2-furyl)methyl]-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-3-pyrrolidinecarboxamide    -   (3R,4S)-N-hydroxy-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)tetrahydro-3-furancarboxamide    -   (3S,4R)-N-hydroxy-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)tetrahydro-3-furancarboxamide    -   (3S,4S)-N-hydroxy-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-1-(1,3-thiazol-2-ylmethyl)-3-pyrrolidinecarboxamide    -   (3S,4S)-1-acetyl-N-hydroxy-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-3-pyrrolidinecarboxamide    -   (3S,4S)-N-hydroxy-1-isobutyryl-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-3-pyrrolidinecarboxamide    -   (3S,4S)-N-hydroxy-1-(3-methylbutanoyl)-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-3-pyrrolidinecarboxamide    -   (3S,4S)-1-(cyclopropylcarbonyl)-N-hydroxy-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-3-pyrrolidinecarboxamide    -   (3S,4S)-1-(cyclobutylcarbonyl)-N-hydroxy-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-3-pyrrolidinecarboxamide    -   (3S,4S)-N-hydroxy-1-(methoxyacetyl)-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-3-pyrrolidinecarboxamide    -   (3S,4S)-1-(2-furoyl)-N-hydroxy-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-3-pyrrolidinecarboxamide    -   (3S,4S)-N-hydroxy-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-1(2-thienylcarbonyl)-3-pyrrolidinecarboxamide    -   (3S,4S)-N-hydroxy-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-1-propionyl-3-pyrrolidinecarboxamide    -   (3R,4S)-4-{[4-(2-butynyloxy)benzoyl]amino}-N-hydroxy-tetrahydro-3-furancarboxamide    -   N-{(1R,2S)-2-[(hydroxyamino)carbonyl]-4-oxocyclopentyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide    -   N-{(1R,2S,4R)-4-hydroxy-2-[(hydroxyamino)carbonyl]cyclopentyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide    -   N-{(1R,2S,4S)-4-hydroxy-2-[(hydroxyamino)carbonyl]cyclopentyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide    -   (3S,4S)-N-hydroxy-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-1-tetrahydro-2H-pyran-4-yl-3-pyrrolidinecarboxamide    -   methyl        (3S,4S)-3-[(hydroxyamino)carbonyl]-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-1-pyrrolidinecarboxylate    -   ethyl        (3S,4S)-3-[(hydroxyamino)carbonyl]-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-1-pyrrolidinecarboxylate    -   propyl        (3S,4S)-3-[(hydroxyamino)carbonyl]-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-1-pyrrolidinecarboxylate    -   allyl        (3S,4S)-3-[(hydroxyamino)carbonyl]-4-({4-[(2-itethyl-4-quinolinyl)methoxy]benzoyl}amino)-1-pyrrolidinecarboxylate    -   isopropyl        (3S,4S)-3-[(hydroxyamino)carbonyl]-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-1-pyrrolidinecarboxylate    -   2-propynyl        (3S,4S)-3-[(hydroxyamino)carbonyl]-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-1-pyrrolidinecarboxylate    -   2-butynyl        (3S,4S)-3-[(hydroxyamino)carbonyl]-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-1-pyrrolidinecarboxylate    -   3-butenyl        (3S,4S)-3-[(hydroxyamino)carbonyl]-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-1-pyrrolidinecarboxylate    -   benzyl        (3S,4S)-3-[(hydroxyamino)carbonyl]-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-1-pyrrolidinecarboxylate    -   N-{(1R,2S)-4-(dimethylamino)-2-[(hydroxyamino)carbonyl]cyclopentyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide    -   (3S,4S)-4-{[4-(2-butynyloxy)benzoyl]amino}-N-hydroxy-1-isopropyl-3-pyrrolidinecarboxamide    -   N-{(1R,2S)-4,4-difluoro-2-[(hydroxyamino)carbonyl]cyclopentyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide    -   (3S,4S)-N-hydroxy-1-isopropyl-4-{[4-(2-methylphenoxy)benzoyl]amino}-3-pyrrolidinecarboxamide    -   cis-N-hydroxy-2-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-1-cyclopentanecarboxamide    -   trans-N-hydroxy-2-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-1-cyclopentanecarboxamide    -   (1S,2R)-N-hydroxy-2-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-1-cyclopentanecarboxamide    -   (1R,2S)-N-hydroxy-2-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-1-cyclopentanecarboxamide    -   cis-N-hydroxy-2-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-1-cyclohexanecarboxamide    -   trans-N-hydroxy-2-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-1-cyclohexanecarboxamide    -   trans-1-[[(1,1-dimethylethyl)oxy]carbonyl]-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-pyrrolidinecarboxamide    -   trans-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-pyrrolidinecarboxamide    -   cis-1-[[(1,1-dimethylethyl)oxy]carbonyl]-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-pyrrolidinecarboxamide    -   cis-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-pyrrolidinecarboxamide    -   (3S,4R)-1-[[(1,1-dimethylethyl)oxy]carbonyl]-N-hydroxy-4-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-3-piperidinecarboxamide    -   (3S,4S)-1-[[(1,1-dimethylethyl)oxy]carbonyl]-N-hydroxy-4-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-3-piperidinecarboxamide    -   (3S,4S)-N-hydroxy-4-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-3-piperidinecarboxamide    -   (3S,4R)-N-hydroxy-4-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-3-piperidinecarboxamide    -   (3S,4R)-1-[(butoxy)carbonyl]-N-hydroxy-4-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-3-piperidinecarboxamide    -   (3S,4R)-N-hydroxy-1-[[(1-methylethyl)oxy]carbonyl]-4-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-3-piperidinecarboxamide    -   (3S,4R)-N-hydroxy-1-(methylsulfonyl)-4-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-3-piperidinecarboxamide    -   (3S,4R)-N-hydroxy-4-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-1-(phenylsulfonyl)-3-piperidinecarboxamide    -   (3S,4R)-1-acetyl-N-hydroxy-4-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-3-piperidinecarboxamide    -   (3S,4R)-1-benzoyl-N-hydroxy-4-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-3-piperidinecarboxamide    -   (3S,4R)-1-(2,2-dimethylpripionyl)-N-hydroxy-4-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-3-piperidinecarboxamide    -   (3S,4R)-1-(3,3-dimethylbutanoyl)-N-hydroxy-4-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-3-piperidinecarboxamide    -   (3S,4R)-N-hydroxy-4-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-1-(4-morpholinecarbonyl)-3-piperidinecarboxamide    -   (3S,4R)-1-(dimethylcarbamyl)-N-hydroxy-4-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-3-piperidinecarboxamide    -   (3S,4R)-N-hydroxy-1-methyl-4-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-3-piperidinecarboxamide    -   (3S,4R)-1-ethyl-N-hydroxy-4-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-3-piperidinecarboxamide    -   (3S,4R)-N-hydroxy-4-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-1-propyl-3-piperidinecarboxamide    -   (3S,4R)-N-hydroxy-1-(1-methylethyl)-4-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-3-piperidinecarboxamide    -   (3S,4R)-1-(cyclopropylmethyl)-N-hydroxy-4-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-3-piperidinecarboxamide    -   (3S,4R)-1-(2,2-dimethylpropyl)-N-hydroxy-4-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-3-piperidinecarboxamide    -   (3S,4R)-1-benzyl-N-hydroxy-4-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-3-piperidinecarboxamide    -   (3S,4R)-1-(2-thiazolylmethyl)-N-hydroxy-4-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-3-piperidinecarboxamide    -   (3S,4S)-1-[[(1,1-dimethylethyl)oxy]carbonyl]-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide    -   (3R,4S)-1-[[(1,1-dimethylethyl)oxy]carbonyl]-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide    -   (3R,4S)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide    -   (3S,4S)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide    -   (3S,4S)-N-hydroxy-1-[[(2-methylpropyl)oxy]carbonyl]-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide    -   (3S,4S)-N-hydroxy-1-(methoxycarbohyl)-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide    -   (3S,4S)-N-hydroxy-1-[(1-methylethoxy)carbonyl]-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide    -   (3S,4S)-N-hydroxy-1-(methylsulfonyl)-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide    -   (3S,4S)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-1-(phenylsulfonyl)-4-piperidinecarboxamide    -   (3S,4S)-1-(3,3-dimethylbutanoyl)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide    -   (3S,4S)-1-(2,2-dimethylpropionyl)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide    -   (3S,4S)-1-benzoyl-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide    -   (3S,4S)-1-[(pyridin-3-yl)carbonyl]-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide    -   (3S,4S)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-1-(2-thiophenecarbonyl)-4-piperidinecarboxamide    -   (3S,4S)-1-(dimethylcarbamyl)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide    -   (3S,4S)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-1-(4-morpholinecarbonyl)-4-piperidinecarboxamide    -   (3S,4S)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-1-[[2-(2-thienyl)ethyl]carbamyl]-4-piperidinecarboxamide    -   (3S,4S)-1-[(1,1-dimethylethyl)carbamyl]-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide    -   (3S,4S)-N-hydroxy-1-methyl-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide    -   (3S,4S)-1-ethyl-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide    -   (3S,4S)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-1-propyl-4-piperidinecarboxamide    -   (3S,4S)-N-hydroxy-1-(1-methylethyl)-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide    -   (3S,4S)-1-cyclobutyl-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide    -   (3S,4S)-1-butyl-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide    -   (3S,4S)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-1-(2-methylpropyl)-4-piperidinecarboxamide    -   (3S,4S)-1-(cyclopropylmethyl)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide    -   (3S,4S)-1-(2,2-dimethylpropyl)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide    -   (3S,4S)-1-cyclopentyl-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide    -   (3S,4S)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-1-(4-tetrahydropyranyl)-4-piperidinecarboxamide    -   (3S,4S)-1-benzyl-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide    -   (3S,4S)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-1-(2-thiazolylmethyl)-4-piperidinecarboxamide    -   (3S,4S)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-1-(4-pyridinylmethyl)-4-piperidinecarboxamide    -   (3S,4S)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-1-(2-pyridinylmethyl)-4-piperidinecarboxamide    -   (3S,4S)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-1-(3-pyridinylmethyl)-4-piperidinecarboxamide    -   (3S,4S)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-1-(trans-3-phenyl-2-propenyl)-4-piperidinecarboxamide    -   (3S,4S)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-1-phenyl-4-piperidinecarboxamide    -   (3R,4S)-1-(2,2-dimethylpropionyl)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide    -   (3R,4S)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-1-methyl-4-piperidinecarboxamide    -   (3R,4S)-1-(dimethylcarbamyl)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide    -   (3S,4S)-1-hexyl-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide    -   (3S,4S)-1-(2-fluoroethyl)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide    -   (3S,4S)-1-(2,2-difluoroethyl)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide    -   (3S,4S)-N-hydroxy-1-(1-methylpropyl)-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide    -   (3S,4S)-1-(1-ethylpropyl)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide    -   (3S,4S)-1-[1-[[(1,1-dimethylethyl)oxy]carbonyl]-4-tetrahydropiperidinyl]-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide    -   (3S,4S)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-1-(4-tetrahydropiperidinyl)-4-piperidinecarboxamide    -   (3S,4S)-1-[1-[[(1,1-dimethylethyl)oxy]carbonyl]-3-tetrahydropyrrolidinyl]-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide    -   (3S,4S)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-1-(3-tetrahydropyrrolidinyl)-4-piperidinecarboxamide    -   (3S,4S)-1-(1,1-dimethyl-2-propynyl)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide    -   (3S,4S)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-1-(3-thiophenylmethyl)-4-piperidinecarboxamide    -   (3S,4S)-N-hydroxy-1-(1-methylethyl)-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-1-oxo-4-piperidinecarboxamide    -   (3S,4S)-N-hydroxy-1-(1-methylethyl)-3-[[[4-[(2-methyl-1-oxo-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide    -   (3S,4S)-N-hydroxy-1-(1-methylethyl)-3-[[[4-[(2-methyl-1-oxo-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-1-oxo-4-piperidinecarboxamide    -   (3S,4S)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-1-[2-(4-morpholinyl)-2-oxoethyl]-4-piperidinecarboxamide    -   (3S,4S)-1-[2-(N,N-dimethylamino)-2-oxoethyl]-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide    -   (3S,4S)-1-(t-butylsulfonyl)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide    -   (3S,4S)-1-(t-butylsulfonyl)-N-hydroxy-3-[[[4-[(2-methyl-1-oxo-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide    -   (3S,4S)-1-(benzenesulfonyl)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide    -   (3S,4S)-1-(t-butylsulfinyl)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide    -   (3S,4S)-N-hydroxy-1-(2-hydroxylethyl)-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide    -   (3S,4S)-1-[2-[[[(1,1-dimethylethyl)oxy]carbonyl]amino]ethyl]-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide    -   (3S,4S)-1-(2-aminoethyl)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide    -   (3S,4S)-1-[2-(N,N-dimethylamino)ethyl]-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide    -   (3S,4S)-1-[(2S)-2-aminopropyl]-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide    -   (3S,4S)-1-[(2R)-2-amino-3-hydroxypropyl]-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide    -   (3S,4S)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-1-[[(2R)-2-pyrrolidinyl]methyl]-4-piperidinecarboxamide    -   (3S,4R)-N-hydroxy-1-(2-hydroxylethyl)-4-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-3-piperidinecarboxamide    -   (3S,4R)-1-(2-aminoethyl)-N-hydroxy-4-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-3-piperidinecarboxamide    -   (3S,4R)-1-cyclobutyl-N-hydroxy-4-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-3-piperidinecarboxamide    -   (3R,4R)-N-hydroxy-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)tetrahydro-2H-pyran-3-carboxamide    -   (3S,4S)-1-tert-butyl-N-hydroxy-3-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-4-piperidinecarboxamide    -   tert-butyl        2-[(3S,4S)-4-[(hydroxyamino)carbonyl]-3-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)piperidinyl]-2-methylpropanoate    -   2-[(3S,4S)-4-[(hydroxyamino)carbonyl]-3-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)piperidinyl]-2-methylpropanoic        acid    -   methyl        2-[(3S,4S)-4-[(hydroxyamino)carbonyl]-3-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)piperidinyl]-2-methylpropanoate    -   (3S,4S)-N-hydroxy-3-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-1-[2-(4-morpholinyl)-2-oxoethyl]-4-piperidinecarboxamide    -   (3S,4S)-1-[2-(dimethylamino)-2-oxoethyl]-N-hydroxy-3-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-4-piperidinecarboxamide    -   (3S,4S)-1-(1,1-dimethyl-2-propenyl)-N-hydroxy-3-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-4-piperidinecarboxamide    -   (3S,4S)-N-hydroxy-3-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-1-tert-pentyl-4-piperidinecarboxamide    -   (3S,4S)-N-hydroxy-3-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-1-(2-propynyl)-4-piperidinecarboxamide    -   (3S,4S)-1-allyl-N-hydroxy-3-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-4-piperidinecarboxamide    -   (3S,4S)-N-hydroxy-1-(1-methyl-2-propynyl)-3-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-4-piperidinecarboxamide    -   (3S,4S)-N-hydroxy-1-(1-methyl-2-propenyl)-3-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-4-piperidinecarboxamide    -   N-{(1R,2S)-4,5-dihydroxy-2-[(hydroxyamino)carbonyl]cyclohexyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide    -   (5S)-N-hydroxy-5-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-2-oxo-4-piperidinecarboxamide    -   (3S,4S)-N-hydroxy-3-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-2-oxo-4-piperidinecarboxamide    -   (3S,4S)-3-{[4-(2-butynyloxy)benzoyl]amino}-N-hydroxy-1-isopropyl-4-piperidinecarboxamide    -   (3S,4S)-3-{[4-(2-butynyloxy)benzoyl]amino}-N-hydroxy-4-piperidinecarboxamide    -   tert-butyl        (3S,4S)-4-[(hydroxyamino)carbonyl]-3-({4-[(2-methyl-3-pyridinyl)methoxy]benzoyl}amino)-1-piperidinecarboxylate    -   (3S,4S)-N-hydroxy-3-({4-[(2-methyl-3-pyridinyl)methoxy]benzoyl}amino)-4-piperidinecarboxamide    -   tert-butyl        (3S,4S)-3-({4-[(2,5-dimethylbenzyl)oxy]benzoyl}amino)-4-[(hydroxyamino)carbonyl]-1-piperidinecarboxylate    -   (3S,4S)-3-({4-[(2,5-dimethylbenzyl)oxy]benzoyl}amino)-N-hydroxy-4-piperidinecarboxamide    -   (cis,cis)-3-Amino-2-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-(N-hydroxy)cyclohexylcarboxamide    -   (cis,cis)-3-Methylamino-2-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-(N-hydroxy)cyclohexylcarboxamide    -   (cis,cis)-3-Dimethylmino-2-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-1-(N-hydroxy)cyclohexylcarboxamide    -   (cis,trans)-3-Amino-2-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-1-(N-hydroxy)cyclohexylcarboxamide    -   (cis,trans)-3-Dimethylmino-2-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-(N-hydroxy)cyclohexylcarboxamide    -   (cis,trans)-3-(1-Methyl-1-ethylmino)-2-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-(N-hydroxy)cyclohexylcarboxamide    -   (cis,trans)-3-Methylamino-2-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-(N-hydrloxy)cyclohexylcarboxamide    -   (cis,cis)-3-Hydroxy-2-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-(N-hydroxy)cyclohexylcarboxamide    -   N-{cis-2-[(Hydroxyamino)carbonyl]cyclopentyl}-4-{[(2-methyl-4-quinolinyl)methyl]amino}benzamide    -   N-{cis-2-[(Hydroxyamino)carbonyl]cyclopentyl}-4-{methyl[(2-methyl-4-quinolinyl)methyl]amino}benzamide    -   N-{cis-2-[(Hydroxyamino)carbonyl]cyclopentyl}-4-(3-phenyl-4,5-dihydro-5-isoxazolyl)benzamide    -   N-{cis-2-[(Hydroxyamino)carbonyl]cyclopentyl}-4-[3-(4-pyridinyl)-4,5-dihydro-5-isoxazolyl]benzamide    -   N-{cis-2-[(Hydroxyamino)carbonyl]cyclopentyl}-4-[3-(3-pyridinyl)-4,5-dihydro-5-isoxazolyl]benzamide    -   N-{cis-2-[(Hydroxyamino)carbonyl]cyclopentyl}-4-[3-(2-pyridinyl)-4,5-dihydro-5-isoxazolyl]benzamide    -   N-{cis-2-[(Hydroxyamino)carbonyl]cyclopentyl}-4-[3-(4-quinolinyl)-4,5-dihydro-5-isoxazolyl]benzamide    -   4-[3-(2,6-Dimethyl-4-pyridinyl)-4,5-dihydro-5-isoxazolyl]-N-{cis-2-[(hydroxyamino)carbonyl]cyclopentyl}benzamide    -   N-{cis-2-[(Hydroxyamino)carbonyl]cyclopentyl}-3-methoxy-4-[3-(4-pyridinyl)-4,5-dihydro-5-isoxazolyl]benzamide    -   3-Hydroxy-N-{cis-2-[(hydroxyamino)carbonyl]cyclopentyl}-4-[3-(4-pyridinyl)-4,5-dihydro-5-isoxazolyl]benzamide    -   N-{cis-2-[(Hydroxyamino)carbonyl]cyclopentyl}-4-[5-(2-pyridinyl)-4,5-dihydro-3-isoxazolyl]benzamide    -   N-{cis-2-[(Hydroxyamino)carbonyl]cyclopentyl}-4-[5-(4-pyridinyl)-4,5-dihydro-3-isoxazolyl]benzamide    -   N-{4-[(hydroxyamino)carbonyl]-3-pyrrolidinyl}-1-[(2-methyl-4-quinolinyl)methyl]-1H-indole-5-carboxamide    -   N-{2-[(hydroxyamino)carbonyl]cyclopentyl}-1-[(2-methyl-4-quinolinyl)methyl]-1H-indole-5-carboxamide    -   N-hydroxy-3-({6-[(2-methyl-4-quinolinyl)methoxy]-1-naphthoyl}amino)-4-piperidinecarboxamide    -   N-{2-[(hydroxyamino)carbonyl]cyclopentyl}-6-[(2-methyl-4-quinolinyl)methoxy]-1-naphthamide    -   N-{2-[(hydroxyamino)carbonyl]cyclopentyl}-6-[(2-methyl-4-quinolinyl)methoxy]-2-naphthamide    -   N-{2-[(hydroxyamino)carbonyl]cyclopentyl}-6-[(2-methyl-4-quinolinyl)methoxy]-1,2,3,4-tetrahydro-1-isoquinolinecarboxamide    -   N-{2-[(hydroxyamino)carbonyl]cyclopentyl}-1-[(2-methyl-4-quinolinyl)methyl]-1H-benzimidazole-5-carboxamide    -   N-{2-[(hydroxyamino)carbonyl]cyclopentyl}-1-[(2-methyl-4-quinolinyl)methyl]-1H-indole-4-carboxamide    -   (±)-cis-N-hydroxy-2-[[4-[(2-methyl-4-quinolinyl)methoxy]benzoyl]amino]-1-cycloheptanecarboxamide    -   (±)-trans-N-hydroxy-2-[[4-[(2-methyl-4-quinolinyl)methoxy]benzoyl]amino]-1-cycloheptanecarboxamide    -   (4S,5R)-N-hydroxy-5-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-2-oxohexahydro-1-azepine-4-carboxamide    -   (3S,4S)-N-hydroxy-3-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-7-oxohexahydro-1H-azepine-4-carboxamide    -   (3S,4R)-N-hydroxy-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-7-oxohexahydro-1H-azepine-3-carboxamide    -   (4S,5R)-N-hydroxy-5-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-7-oxohexahydro-1H-azepine-4-carboxamide    -   (2S,3R)-N-hydroxy-3-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-2-pyrrolidinecarboxamide    -   (2R,3R)-N-hydroxy-3-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-2-pyrrolidinecarboxamide,        and    -   tert-butyl        (2S,3R)-2-[(hydroxyamino)carbonyl]-3-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-1-pyrrolidinecarboxylate    -   or a pharmaceutically acceptable salt form thereof.

In another embodiment, the present invention provides a novelpharmaceutical composition, comprising: a pharmaceutically acceptablecarrier and a therapeutically effective amount of a compound of thepresent invention or a pharmaceutically acceptable salt form thereof.

In another embodiment, the present invention provides a novel method fortreating or preventing an inflammatory disorder, comprising:administering to a patient in need thereof a therapeutically effectiveamount of a compound of the present invention or a pharmaceuticallyacceptable salt form thereof.

In another embodiment, the present invention provides a novel method oftreating a condition or disease mediated by MMPs, TNF, aggrecanase, or acombination thereof in a mammal, comprising: administering to the mammalin need of such treatment a therapeutically effective amount of acompound of the present invention or a pharmaceutically acceptable saltform thereof.

In another embodiment, the present invention provides a novel method oftreating, wherein the disease or condition is referred to as acuteinfection, acute phase response, age related macular degeneration,alcoholism, anorexia, asthma, autoimmune disease, autoimmune hepatitis,Bechet's disease, cachexia, calcium pyrophosphate dihydrate depositiondisease, cardiovascular effects, chronic fatigue syndrome, chronicobstruction pulmonary disease, coagulation, congestive heart failure,corneal ulceration, Crohn's disease, enteropathic arthropathy, Felty'ssyndrome, fever, fibromyalgia syndrome, fibrotic disease, gingivitis,glucocorticoid withdrawal syndrome, gout, graft versus host disease,hemorrhage, HIV infection, hyperoxic alveolar injury, infectiousarthritis, inflammation, intermittent hydrarthrosis, Lyme disease,meningitis, multiple sclerosis, myasthenia gravis, mycobacterialinfection, neovascular glaucoma, osteoarthritis, pelvic inflammatorydisease, periodontitis, polymyositis/dermatomyositis, post-ischaemicreperfusion injury, post-radiation asthenia, psoriasis, psoriaticarthritis, pydoderma gangrenosum, relapsing polychondritis, Reiter'ssyndrome, rheumatic fever, rheumatoid arthritis, sarcoidosis,scleroderma, sepsis syndrome, Still's disease, shock, Sjogren'ssyndrome, skin inflammatory diseases, solid tumor growth and tumorinvasion by secondary metastases, spondylitis, stroke, systemic lupuserythematosus, ulcerative colitis, uveitis, vasculitis, and Wegener'sgranulomatosis.

In another embodiment, the present invention provides novel compounds ofthe present invention for use in therapy.

In another embodiment, the present invention provides the use of novelcompounds of the present invention for the manufacture of a medicamentfor the treatment of a condition or disease mediated by MMPs, TNF,aggrecanase, or a combination thereof.

Definitions

The compounds herein described may have asymmetric centers. Compounds ofthe present invention containing an asymmetrically substituted atom maybe isolated in optically active or racemic forms. It is well known inthe art how to prepare optically active forms, such as by resolution ofracemic forms or by synthesis from optically active starting materials.Geometric isomers of double bonds such as olefins and C═N double bondscan also be present in the compounds described herein, and all suchstable isomers are contemplated in the present invention. Cis and transgeometric isomers of the compounds of the present invention aredescribed and may be isolated as a mixture of isomers or as separatedisomeric forms. All chiral, diastereomeric, racemic forms and allgeometric isomeric forms of a structure are intended, unless thespecific stereochemistry or isomeric form is specifically indicated. Allprocesses used to prepare compounds of the present invention andintermediates made therein are considered to be part of the presentinvention.

The term “substituted,” as used herein, means that any one or morehydrogens on the designated atom is replaced with a selection from theindicated group, provided that the designated atom's normal valency isnot exceeded, and that the substitution results in a stable compound.When a substituent is keto (i.e., ═O), then 2 hydrogens on the atom arereplaced. Keto substituents are not present on aromatic moieties. When aring system (e.g., carbocyclic or heterocyclic) is said to besubstituted with a carbonyl group or a double bond, it is intended thatthe carbonyl group or double bond be part (i.e., within) of the ring.

The present invention is intended to include all isotopes of atomsoccurring in the present compounds. Isotopes include those atoms havingthe same atomic number but different mass numbers. By way of generalexample and without limitation, isotopes of hydrogen include tritium anddeuterium. Isotopes of carbon include C-13 and C-14.

When any variable (e.g., R^(b)) occurs more than one time in anyconstituent or formula for a compound, its definition at each occurrenceis independent of its definition at every other occurrence. Thus, forexample, if a group is shown to be substituted with 0-2 R⁶, then saidgroup may optionally be substituted with up to two R⁶ groups and R⁶ ateach occurrence is selected independently from the definition of R⁶.Also, combinations of substituents and/or variables are permissible onlyif such combinations result in stable compounds.

When a bond to a substituent is shown to cross a bond connecting twoatoms in a ring, then such substituent may be bonded to any atom on thering. When a substituent is listed without indicating the atom via whichsuch substituent is bonded to the rest of the compound of a givenformula, then such substituent may be bonded via any atom in suchsubstituent. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds.

As used herein, “alkyl” or “alkylene” is intended to include bothbranched and straight-chain saturated aliphatic hydrocarbon groupshaving the specified number of carbon atoms. C₁₋₁₀ alkyl (or alkylene),is intended to include C₁, C₂, C₃, C₄, C₅, C₆, C₇, C₈, C₉, and C₁₀ alkylgroups. Examples of alkyl include, but are not limited to, methyl,ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, ands-pentyl. “Haloalkyl” is intended to include both branched andstraight-chain saturated aliphatic hydrocarbon groups having thespecified number of carbon atoms, substituted with 1 or more halogen(for example —C_(v)F_(w) where v=1 to 3 and w=1 to (2 v+1)). Examples ofhaloalkyl include, but are not limited to, trifluoromethyl,trichloromethyl, pentafluoroethyl, and pentachloroethyl. “Alkoxy”represents an alkyl group as defined above with the indicated number ofcarbon atoms attached through an oxygen bridge. C₁₋₁₀ alkoxy, isintended to include C₁, C₂, C₃, C₄, C₅, C₆, C₇, C₈, C₉, and C₁₀ alkoxygroups. Examples of alkoxy include, but are not limited to, methoxy,ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy,and s-pentoxy. “Cycloalkyl” is intended to include saturated ringgroups, such as cyclopropyl, cyclobutyl, or cyclopentyl. C₃₋₇cycloalkyl, is intended to include C₃, C₄, C₅, C₆, and C₇ cycloalkylgroups. “Alkenyl” or “alkenylene” is intended to include hydrocarbonchains of either a straight or branched configuration and one or moreunsaturated carbon-carbon bonds which may occur in any stable pointalong the chain, such as ethenyl and propenyl. C₂₋₁₀ alkenyl (oralkenylene), is intended to include C₂, C₃, C₄, C₅, C₆, C₇, C₈, C₉, andC₁₀ alkenyl groups. “Alkynyl” or “alkynylene” is intended to includehydrocarbon chains of either a straight or branched configuration andone or more triple carbon-carbon bonds which may occur in any stablepoint along the chain, such as ethynyl and propynyl. C₂₋₁₀ alkynyl (oralkynylene), is intended to include C₂, C₃, C₄, C₅, C₆, C₇, C₈, C₉, andC₁₀ alkynyl groups.

“Halo” or “halogen” as used herein refers to fluoro, chloro, bromo, andiodo; and “counterion” is used to represent a small, negatively chargedspecies such as chloride, bromide, hydroxide, acetate, and sulfate.

As used herein, “carbocycle” or “carbocyclic residue” is intended tomean any stable 3, 4, 5, 6, or 7-membered monocyclic or bicyclic or 7,8, 9, 10, 11, 12, or 13-membered bicyclic or tricyclic, any of which maybe saturated, partially unsaturated, or aromatic. Examples of suchcarbocycles include, but are not limited to, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl,[3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane,[2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl,and tetrahydronaphthyl.

As used herein, the term “heterocycle” or “heterocyclic group” isintended to mean a stable 5, 6, or 7-membered monocyclic or bicyclic or7, 8, 9, or 10-membered bicyclic heterocyclic ring which is saturated,partially unsaturated or unsaturated (aromatic), and which consists ofcarbon atoms and 1, 2, 3, or 4 heteroatoms independently selected fromthe group consisting of N, O and S and including any bicyclic group inwhich any of the above-defined heterocyclic rings is fused to a benzenering. The nitrogen and sulfur heteroatoms may optionally be oxidized.The nitrogen atom may be substituted or unsubstituted (i.e., N or NRwherein R is H or another substituent, if defined). The heterocyclicring may be attached to its pendant group at any heteroatom or carbonatom that results in a stable structure. The heterocyclic ringsdescribed herein may be substituted on carbon or on a nitrogen atom ifthe resulting compound is stable. A nitrogen in the heterocycle mayoptionally be quaternized. It is preferred that when the total number ofS and O atoms in the heterocycle exceeds 1, then these heteroatoms arenot adjacent to one another. It is preferred that the total number of Sand O atoms in the heterocycle is not more than 1. As used herein, theterm “aromatic heterocyclic group” or “heteroaryl” is intended to mean astable 5, 6, or 7-membered monocyclic or bicyclic or 7, 8, 9, or10-membered bicyclic heterocyclic aromatic ring which consists of carbonatoms and 1, 2, 3, or 4 heterotams independently selected from the groupconsisting of N, O and S. It is to be noted that total number of S and Oatoms in the aromatic heterocycle is not more than 1.

Examples of heterocycles include, but are not limited to, acridinyl,azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl,benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl,carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl,cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl,indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl,isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl,isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl,octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl,phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl,piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl,pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl,pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole,pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl,pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl,quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl,tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl,1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl,1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl,thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl,1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, andxanthenyl. Also included are fused ring and spiro compounds containing,for example, the above heterocycles.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof. Examples of pharmaceuticallyacceptable salts include, but are not limited to, mineral or organicacid salts of basic residues such as amines; and alkali or organic saltsof acidic residues such as carboxylic acids. The pharmaceuticallyacceptable salts include the conventional non-toxic salts or thequaternary ammonium salts of the parent compound formed, for example,from non-toxic inorganic or organic acids. For example, suchconventional non-toxic salts include those derived from inorganic acidssuch as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, andnitric; and the salts prepared from organic acids such as acetic,propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric,ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic,benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric,toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, andisethionic.

The pharmaceutically acceptable salts of the present invention can besynthesized from the parent compound which contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, nonaqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare preferred. Lists of suitable salts are found in Remington'sPharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa.,1985, p. 1418, the disclosure of which is hereby incorporated byreference.

Since prodrugs are known to enhance numerous desirable qualities ofpharmaceuticals (e.g., solubility, bioavailability, manufacturing, etc .. . ) the compounds of the present invention may be delivered in prodrugform. Thus, the present invention is intended to cover prodrugs of thepresently claimed compounds, methods of delivering the same andcompositions containing the same. “Prodrugs” are intended to include anycovalently bonded carriers which release an active parent drug of thepresent invention in vivo when such prodrug is administered to amammalian subject. Prodrugs the present invention are prepared bymodifying functional groups present in the compound in such a way thatthe modifications are cleaved, either in routine manipulation or invivo, to the parent compound. Prodrugs include compounds of the presentinvention wherein a hydroxy, amino, or sulfhydryl group is bonded to anygroup that, when the prodrug of the present invention is administered toa mammalian subject, it cleaves to form a free hydroxyl, free amino, orfree sulfhydryl group, respectively. Examples of prodrugs include, butare not limited to, acetate, formate and benzoate derivatives of alcoholand amine functional groups in the compounds of the present invention.

“Stable compound” and “stable structure” are meant to indicate acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent.

“Therapeutically effective amount” is intended to include an amount of acompound of the present invention or an amount of the combination ofcompounds claimed effective to inhibit a desired metalloprotease in ahost. The combination of compounds is preferably a synergisticcombination. Synergy, as described for example by Chou and Talalay, Adv.Enzyme Regul. 22:27-55 (1984), occurs when the effect (in this case,inhibition of the desired target) of the compounds when administered incombination is greater than the additive effect of the compounds whenadministered alone as a single agent. In general, a synergistic effectis most clearly demonstrated at suboptimal concentrations of thecompounds. Synergy can be in terms of lower cytotoxicity, increasedantiviral effect, or some other beneficial effect of the combinationcompared with the individual components.

Synthesis

The compounds of the present invention can be prepared in a number ofways well known to one skilled in the art of organic synthesis. Thecompounds of the present invention can be synthesized using the methodsdescribed below, together with synthetic methods known in the art ofsynthetic organic chemistry, or variations thereon as appreciated bythose skilled in the art. Preferred methods include, but are not limitedto, those described below. All references cited herein are herebyincorporated in their entirety herein by reference.

The novel compounds of this invention may be prepared using thereactions and techniques described in this section. The reactions areperformed in solvents appropriate to the reagents and materials employedand are suitable for the transformations being effected. Also, in thedescription of the synthetic methods described below, it is to beunderstood that all proposed reaction conditions, including choice ofsolvent, reaction atmosphere, reaction temperature, duration of theexperiment and work up procedures, are chosen to be the conditionsstandard for that reaction, which should be readily recognized by oneskilled in the art. It is understood by one skilled in the art oforganic synthesis that the functionality present on various portions ofthe molecule must be compatible with the reagents and reactionsproposed. Such restrictions to the substituents which are compatiblewith the reaction conditions will be readily apparent to one skilled inthe art and alternate methods must then be used.

A variety of compounds of formula (I) wherein A is hydroxamic acid groupare prepared from the corresponding esters via several routes known inthe literature (Scheme 1). The methyl ester of 1 (R¹¹=Me) is directlyconverted to hydroxamic acid 2 by treatment with hydroxylamine underbasic conditions such as KOH or NaOMe in solvents such as methanol. Themethyl ester of 1 (R¹¹=Me) can also be converted to O-benzyl protectedhydroxamic acid with O-benzylhydroxylamine under similar conditions orusing Weinreb's trimethylalluminum conditions (Levin, J. I.; Turos, E.;Weinreb, S. M. Syn. Commun. 1982, 12, 989) or Roskamp'sbis[bis(trimethylsilyl)amido]tin reagent (Wang, W.-B.; Roskamp, E. J. J.Org. Chem. 1992, 57, 6101). The benzyl ether is removed by methods wellknown in the literature such as hydrogenation using palladium on bariumsulfate in hydrogen, to give compound 2. Alternatively, 2 can beprepared through the carboxylic intermediate 3. Carboxylic acid 3 isconverted to 2 via coupling with hydroxylamine, or O-benzylhydroxylaminefollowed by deprotection.

The β-amino acid moiety in formula (I) can be synthesized following avariety of literature routes as reviewed in “Enantioselective Synthesisof β-Amino Acids” (E. Juaristi, Ed. Wiley-VCH, 1997). One representativeapproach using Davies protocol is summarized in Scheme 2 (J. Chem. Soc.Perkin Trans I, 1994, 1411). Michael addition of lithium amide 5 to 4gives cis product 6. The stereochemical configuration of 6 is governedby the chirality of 5. De-benzylation of 6 provides cis-β-amino acid 7.The trans-β-amino acid 9 can be prepared by epimerization of 6 followedby de-benzylation. Since both amine enantiomers of 5 are commerciallyavailable, this approach provides ready access to both cis and transisomers (7 and 9), as well as their antipodes.

Alternatively, these β-amino acids can be prepared from thecorresponding dicarboxylate derivatives (Scheme 3). The dicarboxylatederivatives can be de-symmetrized through enzymatic resolution (for anexample with lipase, see Gais, H.-J. et al, J. Am. Chem. Soc. 1989, 54,5115), or through chemical resolution (for an example with TADOLates,see Seebach, D. et al, Angew Chem Int. Ed. Engl. 1995, 34, 2395). Theoptically pure mono-ester 11 is converted to Cbz protected β-amino acidester 12 through Curtius rearrangement (for a related example, seeKobayashi, S. et al, Tetrahedron Lett. 1984, 25, 2557).

Removal of Cbz protecting group provides cis amino acid ester 13. Thecorresponding trans analogue of 13 can be prepared from the ester oftrans di-carboxylic acid of 10 following same sequence.

A series of compounds of formula (I) wherein ring B is pyrrolidine areprepared following the sequence outlined in Scheme 4. Pyrrolidine 15 isprepared following a dipolar addition procedure documented in theliterature (Joucla, M.; Mortier, J., J. Chem. Commun. 1985, 1566).Protecting group manipulations and Curtius rearrangement (for a relatedexample, see Kobayashi, S. et al, Tetrahedron Lett. 1984, 25, 2557) giveintermediate 17. Hydrogenolysis gives amino acid ester 18. 18 is coupledwith acid 20 to provide 21 with R¹ as H. To prepare analogues of 21 whenR¹ is not a hydrogen, 18 is first converted to 19 by alkylation orreductive amination, then coupled with 20. The pyrrolidine nitrogen in21 is unmasked and functionalized to various tertiary amines, amides,carbamides, ureas, sulfonamides and sulfonyl ureas following procedureswell known in the literature. Ester 23 is converted to hydroxamic acidfollowing sequence outlined in Scheme 1. Following the same sequence,the cis isomer of 23 can be prepared using benzyl methyl maleate as thestarting material.

A series of compounds of formula (I) wherein ring B is piperidine areprepared following the sequence outlined in Scheme 5. The β-amino acidmoiety is prepared by reduction of enamine 27. Optically pureα-methylbenzylamine (26) is used to induce diastereoselectivity in thereduction (Cimarelli, C. et. al, J. Org. Chem. 1996, 61, 5557).Hydrogenolysis gives amino acid ester 29. 29 is coupled with acid 20 toprovide 31 with R¹ as H. To prepare analogues of 31 when R¹ is not ahydrogen, 29 is first converted to 30 by alkylation or reductiveamination, then coupled with 20. The piperidine nitrogen in 31 isunmasked and functionalized to various tertiary amines, amides,carbamides, ureas, sulfonamides and sulfonyl ureas following procedureswell known in the literature. Ester 33 is converted to hydroxamic acidfollowing sequence outlined in Scheme 1. Regio-isomers of 33 withpiperidine nitrogen transposed to other positions are prepared followinga similar sequence. The antipode of 33 can be prepared using the Senantiomer of 26. The trans-isomer of 33 is prepared by epimerization of31 or 33 under basic conditions (e.g., DBU, PhMe, at reflux).

A series of compounds of formula (I) wherein ring B is piperidine andR^(2a) is hydroxy are prepared following the sequence outlined in Scheme6. Ketone 34 is converted to enol triflate 35 following McMurrytriflimide conditions (McMurry, J. E.; Scott, W. J. Tetrahedron Lett.1983, 24, 979). Palladium-catalyzed carbonylation in methanol providesmethyl ester 36. Epoxidation, epoxide opening with NaN3 andhydrogenation give intermediate 39 with amino and ester groups in cisrelationship. The isomer with trans stereochemistry (43) is preparedusing Sharpless asymmetric aminohydroxylation and subsequent removal ofCbz group (Li, G.; Angert, H. H.; Sharpless, K. B. Angew. Chem. Int. Ed.Engl. 1996, 35, 2813). Coupling of 39 and 43 with acid 20 provides 40and 44, respectively. Esters 40 and 44 are converted to hydroxamic acidsfollowing sequence outlined in Scheme 1.

A series of compounds of formula (I) wherein A is N-formylhydroxylaminogroup are prepared following the sequence outlined in Scheme 7. Startingfrom trans-hydroxy ester 45, Wenreib or Roskamp amide formation withO-t-butylhydroxylamine gives 46 (Levin, J. I.; Turos, E.; Weinreb, S. M.Syn. Commun. 1982, 12, 989 and Wang, W.-B.; Roskamp, E. J. J. Org. Chem.1992, 57, 6101). β-Lactam is formed under Mitsunobu conditions(Mitsunobu, O. Synthesis, 1981, 1). Opening of lactam 47 withmethylamine followed by N-formylation provide 49. The N-methyl amidemoiety of 49 is converted to carboxylic acid by nitrosation with N2O4 orNaNO2, and hydrolysis with LiOOH (Evans, D. A.; Carter, P. H.; Dinsmore,C. J.; Barrow, J. C.; Katz, J. L.; Kung, D. W. Tetrahedron Lett. 1997,38, 4535). Acid 50 is converted to 53 as described previously. Acidhydrolysis of t-Butyl group in 53 completes the synthesis.

A series of compounds of formula (I) wherein A is mercaptomethyl groupare prepared following the sequence outlined in Scheme 8. Saponificationand hydroboration of 55 give alcohol 57. Mitsunobu reaction withthioacetic acid followed by lithium hydroxide hydrolysis provides thedesired thiol 59.

A variety of compounds of formula (I) wherein Z-U^(a)—X^(a)—Y^(a)-Z^(a)is a functionalized phenyl group can be prepared by methods described inScheme 9. Intermediate 60, available from schemes described previously,is converted to phenol 61 by hydrogenolysis. Phenol 61 is used as commonintermediates for structure diversification. Reaction of 61 with R¹⁰—Xprovides 62, an alternative is the reaction of 61 with R¹⁰—OH underMitsunobu conditions to produce 62. R¹⁰ can be appended directly to thearomatic ring by converting 61 to an aryl triflate then reaction with anorganometallic in the presence of a palladium (O) catalyst to give 63.61 can also be reacted with acyl halides or isocyanates to afford 66.Biaryl ethers 65 can be produced by treatment of 61 with aryl boronicacids in the presence of a copper catalyst. Esters 62-63 and 65-66 areconverted to the hydroxamic acids following the sequences outlined inScheme 1.

Compounds of formula 76 can be prepared starting from the commerciallyavailable 3-hydroxy-2-nitrobenzoic acid 67 (Scheme 10). Conversion ofthe carboxylic acid to an ester such as an ethyl ester 68 can beaccomplished by refluxing in EtOH/benzene in the presence of sulfuricacid. Ester 68 can be reduced to a saturated cyclohexyl ring 69 byhydrogenation in acidic aqueous solution using a catalyst such as PtO₂.Coupling of 69 with a benzoic acid derivative 70 using a coupling agentsuch as BOP produces the amide derivative 71 as the major diastereomerwith a cis, cis-stereochemistry. The hydroxyl group of 71 can beoxidized using an oxidizing agent such as the Dess-Martin periodinane togive a ketone derivative 72. Reductive amination of 72 with ammoniumacetate or a primary amine using a reducing agent such as Na(OAc)₃BHaffords the amino derivative 73. After Boc protection at the amino usingdi-tert-butyl-dicarbonate, saponification of the ethyl ester 74 at anelevated temperature using a base such as KOH in MeOH/H₂O followed bycoupling of the resulting carboxylic acid with hydroxylaminehydrochloride using a coupling agent such as BOP produces the hydroxamicacid 75. Removal of the Boc group using an acid such TFA/CH₂Cl₂ or 4 NHCl in dioxane affords the final compounds of formula 76.

Compounds of formula 78 can be obtained by reductive amination of theintermediate 73 with an aldehyde using a reducing agent such asNa(OAc)₃BH followed by conversion of the ethyl ester to a hydroxamate asshown in Scheme 11.

Compounds of formula 80 can be obtained by reductive 5 amination of theintermediate 72 with a cycloamine such as azetidine, pyrrolidine,piperidine or morpholine using a reducing agent such as Na(OAc)₃BHfollowed by conversion of the ethyl ester to a hydroxamate as shown inScheme 12.

Compound of formula 89 can be synthesized starting from the intermediate69 which is coupled with 4-benzyloxybenzoic acid 81 using a couplingagent such as BOP, producing 82 as the major diastereomer with a cis,cis-stereochemistry (Scheme 13). The hydroxyl group can be converted toa sulfonate such as a mesylate 83. Displacement of 83 with sodium azideproduces the azido derivative 84 which is subjected to a hydrogenolysisusing a catalyst such as Pd—C to give the primary amine 85. Mono Bocprotection at the amino group is accomplished by reaction of 85 withdi-tert-butyl-dicarbonate in THF/H₂O using a mixed base such asNaOH/NaHCO₃. Alkylation of 86 with 4-chloromethyl-2-methylquinolineusing a base such as potassium carbonate in acetone at reflux affordsthe intermediate 87. Following saponification using a base such as KOHin MeOH/H₂O at an elevated temperature, the resulting carboxylic acid 88is coupled with hydroxylamine hydrochloride using a coupling agent suchas BOP. Removal of the Boc group using an acid such as TFA/CH₂Cl₂produces the final compound 89.

Compounds of formula 92 can be prepared starting from the intermediate87 (Scheme 14). Saponification using a base such as KOH in MeOH at anelevated temperature followed by deprotection of the Boc group using anacid such as TFA in CH₂Cl₂ produces the amino-carboxylic acidintermediate 90. Reductive amination of 90 with a ketone using areducing agent such as Na(OAc)₃BH produces the secondary amine 91. Thehydroxamic acids of formula 92 can be obtained by coupling thecarboxylic acid with hydroxylamine hydrochloride using a coupling agentsuch as BOP.

Compounds of formula 95 can be obtained by reductive amination of theintermediate 90 with an aldehyde using a reducing agent such asNa(OAc)₃BH followed by conversion of the carboxylic acid to a hydroxamicacid as shown in Scheme 15.

Compounds of formula 103 can be prepared starting from the intermediate85 (Scheme 16). The mono-benzylated amino derivative 97 can be obtainedby reductive amination of the intermediate 85 with excess benzaldehydeusing a reducing agent such as Na(OAc)₃BH followed by hydrogenationunder atmospheric pressure using a catalyst such as Pd—C. Furtheralkylation at the benzylamino group by reductive amination with analdehyde using a reducing agent such as Na(OAc)₃BH produces the tertiaryamino derivative 98. After removal of the benzyl group by hydrogenation,the secondary amine is protected by reaction withdi-tert-butyl-dicarbonate. Alkylation of the phenol derivative 100 with4-chloromethyl-2-methylquinoline is followed by saponification of theethyl ester using a base such as KOH in MeOH at reflux. Conversion ofthe carboxylic acid to a hydroxamic acid followed by acid deprotectionof the Boc group affords compounds of formula 103.

Compounds of formula 108 can be prepared starting from the intermediate83 (Scheme 17). Displacement of 83 with ArOH produces the aryl ether104. After removal of the benzyl group by hydrogenation using a catalystsuch as Pd—C, the phenol moiety is alkylated with4-chloromethyl-2-methylquinoline. Saponification of the ethyl esterusing a base such as KOH in MeOH at reflux followed by coupling of theresulting carboxylic acid with hydroxylamine hydrochloride using acoupling agent such as BOP affords compounds of formula 108.

The 3-hydroxyl analog of formula 110 can be prepared starting from theintermediate 71. Saponification using a base such as LiOH followed bycoupling the resulting carboxylic acid with hydroxylamine hydrochlorideusing a coupling agent such as BOP provides the the final product with acis, cis-stereochemistry.

The cis-trans-diastereomeric analog of 110 can be prepared starting fromthe same intermediate 71. Inversion of the chirality at the 3-hydroxylposition can be accomplished by a Mitsunobu reaction with 4-nitrobenzoicacid. Hydrolysis using a base such as KOH removes the 4-nitrobenzoylmoiety and saponifies the ethyl ester. Coupling of the resultingcarboxylic acid with hydroxylamine hydrochloride using a coupling agentsuch as BOP provides compound of formula 112.

A series of compound of formula (I) where ring B is tetrahydropyran areprepared following the sequence outlined in Scheme 20. Treatment of theenolate of tetrahydropyranone 113 with Mander's reagent provides β-ketoester 114. Condensation of 114 with amine 115 gives enamine 116.Reduction of 116 with sodium (triacetoxy)borohydride proceedsstereoselectively to give desired amine 117. Hydrogenolysis and couplingwith acid 20 provides ester 119. Ester 119 is converted to hydroxamicacid following sequence outline in Scheme 1.

Compounds of formula (I) wherein ring B is a tetrahydrofuran areprepared as outlined in Schemes 21 and 22. Michael addition of thesodium salt of methyl glycolate 120 to methyl acrylate and concomitantDieckman cyclization provides the keto-ester 121. Enamine formation with(R)-α-methylbenzyl amine 115 and diastereoselective reduction gives 123.Hydrogenolysis gives the amino acid ester 124. 124 is coupled to acid 20and converted to the hydroxamate 126.

An alternative preparation (Scheme 22) of the amino acid ester 124begins with the intermediate 121. Enamine formation with NH₄OAc andacetylation gives 128. Asymmetric hydrogenation using a chiral rhodiumcatalyst (J. Am. Cem. Soc. 1995, 117, 9375) and de-acetylation wouldyield 124 that could be converted similarly to hydroxamate 126.

Another procedure for the synthesis of cyclic β-amino acids useful forthe preparation of compounds of formula I uses the well documented [2+2]cycloaddition of chlorosulfonylisocyanate with olefins (Scheme 23, Dhar,D. N.; Murthy, K. S. K. Synthesis 1986, 437-449). When 130 is reactedwith chlorosulfonylisocyanate the resulting β-lactam intermediate 131can be opened to afford cyclic β-amino acids using a variety ofconditions, but most conveniently with chlorotrimethylsilane/methanol.The methyl ester 13 can then be converted to compounds of formula Ifollowed our usual procedure of attaching carboxcylic acid 20 to provide132 then hydroxamic acid 133 is formed by our standard conditions. Thetrans β-amino acids 134 are available by equilibration of cis amideester 132 under basic conditions.

An alternative synthesis of 133 begins with formation of benzylhydroxamate 136 from trans β-hydroxy carboxylate 135 (Scheme 24).Intramolecular cyclization of 136 under Mitsunobu conditions(Bellettini, J. R.; Miller, M. J. Tetrahedron Letters 1997, 38, 167-168)then affords benzyl protected hydroxy β-lactam 137. Removal of thebenzyl group by hydrogenolysis and reduction of the intermediateN-hydroxy β-lactam provides 131, which can be converted to finalproducts as shown in the previous scheme.

A synthesis of cyclic lactam β-amino acids begins conveniently withketone 138 (Scheme 25). Oxime 139 is formed with hydroxylaminehydrochloride, sodium bicarbonate in refluxing methanol and is thentreated with p-toluenesulfonyl chloride to give Beckmann rearrangementprecursor 140. The rearrangement can be driven by a variety ofconditions with silica gel/chloroform providing a straightforward mildprocedure to form lactam 141. Conversion of 141 to hydroxamate 142 usesconditions outline in previous schemes.

Compounds of formula 147 can be prepared using the protocol described inScheme 26. Alkylation of methyl 4-aminobenzoate or methyl4-methylaminobenzoate 143 with 4-chloromethyl-2-methylquinoline usingK₂CO₃ in DMF at 100 ^(□)C produced the secondary or tertiary amine 144.Following saponification, the resulting carboxylic acid 145 was coupledwith a cyclic β-aminoacid derivative using a coupling agent such as BOPto give the amide 146. Conversion of the ester in 146 to a hydroxamicacid using hydroxylamine afforded the final product 147.

Compounds of formula 154 can be prepared according to Scheme 27. Analdehyde 148 was treated with hydroxylamine to provide an oxime 149.Cycloaddition of 149 with an olefin 150 using bleach produced theisoxazoline derivative 151. Hydrolysis of the ester followed by couplingwith a cyclic β-aminoacid derivative afforded the amide 153. Treatmentof 153 with a hydroxylamine solution produced the hydroxamic acid 154.

Compounds of formula 161 can be prepared using the sequence asillustrated in Scheme 28. An aldehyde 155 was treated with hydroxylamineto give an oxime 156. Cycloaddition of 146 with an olefin 157 usingbleach produced the isoxazoline derivative 158. Followingsaponification, the resulting carboxylic acid 159 was condensed with acyclic β-aminoacid to give the amide 160. Treatment of 160 with ahydroxylamine solution afforded the hydroxamic acid 161.

One diastereomer of a compound of Formula I may display superioractivity compared with the others. Thus, the following stereochemistriesare considered to be a part of the present invention.

When required, separation of the racemic material can be achieved byHPLC using a chiral column or by a resolution using a resolving agentsuch as camphonic chloride as in Steven D. Young, et al, AntimicrobialAgents and Chemotheraphy, 1995, 2602-2605. A chiral compound of FormulaI may also be directly synthesized using a chiral catalyst or a chiralligand, e.g., Andrew S. Thompson, et al, Tetr. Lett. 1995, 36,8937-8940.

Other features of the invention will become apparent in the course ofthe following descriptions of exemplary embodiments that are given forillustration of the invention and are not intended to be limitingthereof.

EXAMPLES

Abbreviations used in the Examples are defined as follows: “1×” foronce, “2×” for twice, “3×” for thrice, “° C.” for degrees Celsius, “eq”for equivalent or equivalents, “g” for gram or grams, “mg” for milligramor milligrams, “mL” for milliliter or milliliters, “¹H” for proton, “h”for hour or hours, “M” for molar, “min” for minute or minutes, “MHz” formegahertz, “MS” for mass spectroscopy, “NMR” for nuclear magneticresonance spectroscopy, “rt” for room temperature, “tlc” for thin layerchromatography, “v/v” for volume to volume ratio. “α”, “β”, “R” and “S”are stereochemical designations familiar to those skilled in the art.

Example 1N-{(1R,2S)-2-[(hydroxyamino)carbonyl]cyclopentyl}-2′-(trifluoromethyl)[1,1′-biphenyl]-4-carboxamide

-   (1a) Tetrakis(triphenylphosphine)palladium(0) (168 g, 0.1 eq) was    added to a mixture of methyl-4-iodobenzoate (0.384 g, 1.44 mmol),    2-trifluoromethylphenylboronic acid (0.3 g, 1.1 eq), sodium    carbonate (2 M, 2 eq), ethanol (1.5 mL) and benzene (1.5 mL) at rt.    The mixture was heated to 70° C. for 24 h and cooled to rt. The    mixture was diluted with ether (20 mL) and washed with water and    brine (10 mL each), dried (MgSO₄) and concentrated. Silica gel    column chromatography (ethyl acetate-hexane, 5:95) yielded the    desired product (364 mg, 90%). MS found: (M−H)⁻=279.-   (1b) The ester (364 mg, 1.3 mmol) from reaction (1a), lithium    hydroxide (1 M, 10 eq) and methanol (13 mL) were stirred at 40° C.    for 4.5 h. The pH of the mixture was adjusted to pH=3 with 1 N HCl    and then extracted with ethyl acetate (2×30 mL), washed with brine    (25 mL) dried (MgSO₄) and concentrated. Silica gel column    chromatography (ethyl acetate-hexane, 1:1) yielded the desired    product (247 mg, 71%). MS found: (M−H)⁻=265.-   (1c) BOP reagent (239 mg, 1.2 eq) was added to a mixture of    (1S,2R)-2-carbomethoxycyclopentyl amine hydrochloride (81 mg, 0.45    mmol), the carboxylic acid (120 mg, 1 eq) from reaction (1b),    N,N-diisopropylethylamine (0.12 mL, 2.5 eq) and    N,N-dimethylformamide (2.5 mL) at rt. After 2.5 h at rt saturated    aqueous ammonium chloride (25 mL) was added and the mixture    extracted with ethyl acetate (2×20 mL). The mixture was washed with    water (10 mL), brine (10 mL), dried (MgSO₄) and concentrated. Silica    gel column chromatography (ethyl acetate-hexane, 1:3) yielded the    desired product (147 mg, 83%). MS found: (M+H)⁺=392.-   (1d) Preparation of hydroxylamine/potassium hydroxide solution: A    solution of potassium hydroxide (2.81 g, 1.5 eq) in methanol (7 mL)    was added to a hot solution of hydroxylamine hydrochloride (2.34 g,    33.7 mmol) in methanol (12 mL). After the mixture was cooled to room    temperature, the precipitate was removed by filtration. The filtrate    was used fresh and assumed hydroxylamine concentration of 1.76 M.

The above freshly prepared 1.76 M hydroxylamine solution (0.5 mL, 4 eq)was added to the methyl ester (80 mg, 0.20 mmol) from reaction (1c) inmethanol (1 mL) and stirred at room temperature for 5 h. The mixture wasadjusted to pH 7 with 1 N hydrochloric and diluted with ethyl acetate(10 mL). The organic layer was washed with brine (5 mL), dried (MgSO₄)and concentrated. Reverse phase HPLC purification (gradient elution,water/acetonitrile 85-15 to 10-90) provided the hydroxamic acid (50 mg,63%). MS found: (M+H)⁺=393.

Example 2N-{(1R,2S)-2-[(hydroxyamino)carbonyl]cyclopentyl}-4-[2-(trifluoromethyl)phenoxy]benzamide

-   (2a) 4-hydroxybenzoic acid (240 mg, 1.6 mmol),    2-trifluoromethylphenylboronic acid (300 mg, 1 eq), pyridine (0.68    mL, 5 eq), 4A molecular sieves (100 mg), copper (II) acetate (0.32    g, 1 eq) and dichloromethane (15 mL) were stirred under air    atmosphere for 4 days. The mixture was filtered through Celite and    the bed washed with ethyl acetate-hexane (1:9, 50 mL) and    concentrated. Silica gel column chromatography (ethyl    acetate-hexane, 1:10) yielded the desired product (49 mg, 10%). MS    found: (M+H)⁺=296.-   (2b) Using procedures analogous to those described for reactions    (1b)-(1d), the methyl ester (49 mg, 0.162 mmol) from reaction (2a)    was converted to the desired hydroxamic acid (2.6 mg, 4% for 3    steps). MS found: (M+H)⁺=409.

Example 3N-{(1R,2S)-2-[(hydroxyamino)carbonyl]cyclopentyl}-4-(3-methyl-2-pyridinyl)benzamide

-   (3a) Using procedures analogous to those described for reactions    (1a)-(1d), 4-carbomethoxyphenylboronic acid (0.72 g, 2 eq) and    2-bromo-3-methylpyridine (0.34 g, 2.0 mmol) were converted to the    desired hydroxamic acid (40 mg, 10% for 4 steps). MS found:    (M+H)⁺=340.

Example 4N-{(1R,2S)-2-[(hydroxyamino)carbonyl]cyclopentyl}[1,1′-biphenyl]-4-carboxamide

-   (4a) Using procedures analogous to those described for reactions    (1c)-(1d), the amine hydrochloride (106 mg, 0.59 mmol) and    4-biphenylcarboxylic acid (117 mg, 1 eq) were converted to the    desired hydroxamic acid (46.6 mg, 36% for 2 steps). MS found:    (M+H)⁺=325.

Example 5N-{(1R,2S)-2-[(hydroxyamino)carbonyl]cyclopentyl}-4-phenoxybenzamide

-   (5a) Using procedures analogous to those described for reactions    (1c)-(1d), the amine hydrochloride (111 mg) and 4-phenoxybenzoic    acid (132 mg, 1 eq) were converted to the desired hydroxamic acid    (24.2 mg, 36% for 2 steps). MS found: (M+H)⁺=341.

Example 64-(benzyloxy)-N-{(1R,2S)-2-[(hydroxyamino)carbonyl]cyclopentyl}benzamide

-   (6a) Using procedures analogous to those described for reactions    (1c)-(1d), the amine hydrochloride (101 mg, 0.56 mmol),    4-benzyloxybenzoic acid (129 mg, 1 eq) were converted to the desired    hydroxamic acid (19.1 mg, 26% for 2 steps). MS found: (M+H)⁺=355.

Example 7N-{(1R,2S)-2-[(hydroxyamino)carbonyl]cyclopentyl}-2′-methoxy[1,1′-biphenyl]-4-carboxamide

-   (7a) Using procedures analogous to those described for reactions    (1a)-(1d), 2-methoxyphenylboronic acid (0.163 g, 1.1 eq), methyl    4-iodobenzoate (265 mg, 1.0 mmol) were converted to the desired    hydroxamic acid (30 mg, 9% for 4 steps). MS found: (M+H)⁺=355.

Example 8N-{(1R,2S)-2-[(hydroxyamino)carbonyl]cyclopentyl}-2′-methyl[1,1′-biphenyl]-4-carboxamide

-   (8a) Using procedures analogous to those described for reactions    (1a)-(1d), methyl 4-iodobenzoate (0.100 g, 0.4 mmol) and    2-methylphenylboronic acid (0.066 g, 1.2 eq) were reacted to give    the desired hydroxamic acid (9.5 mg, 7% for 4 steps). MS found:    (M+H)⁺=339.

Example 9N-{(1R,2S)-2-[(hydroxyamino)carbonyl]cyclopentyl}-4-(2-methoxyphenoxy)benzamide

-   (9a) Using procedures analogous to those described for reactions    (2a), (1b)-(1d), 4-hydroxybenzoic acid (152 mg, 1.0 mmol)and    2-methoxyphenylboronic acid (304 mg, 2 eq), were reacted to give the    desired hydroxamic acid (5.1 mg, 14% for 4 steps). MS found:    (M+H)⁺=371.

Example 10N-{(1R,2S)-2-[(hydroxyamino)carbonyl]cyclopentyl}-4-(2-methylphenoxy)benzamide

-   (10a) Using procedures analogous to those described for reactions    (2a), (1b)-(1d), 4-hydroxybenzoic acid (152 mg, 1.0 mmol) and    2-methylphenylboronic acid (272 mg, 2 eq) were reacted to give the    desired hydroxamic acid (23 mg, 7% for 4 steps). MS found:    (M+H)⁺=355.

Example 11N-{(1R,2S)-2-[(hydroxyamino)carbonyl]cyclopentyl}-4-(3-methylphenoxy)benzamide

-   (11a) Using procedures analogous to those described for reactions    (1a)-(1d), methyl 4-iodobenzoate (0.663 g, 0.2.5 mmol) and    3-methylphenylboronic acid (0.408 g, 1.2 eq) were reacted to give    the desired hydroxamic acid (91.9 mg, 46% for 4 steps). MS found:    (M+H)⁺=339.

Example 124-(5,8-dihydro-4-quinolinyl)-N-{(1R,2S)-2-[(hydroxyamino)carbonyl]cyclopentyl}benzamide

-   (12a) Using procedures analogous to those described for reactions    (1a)-(1d), 4-carbomethoxyphenylboronic acid (298 mg, 2 eq) and    4-bromoquinoline were reacted to give the desired hydroxamic acid    (25 mg, 9% for 4 steps). MS found: (M+H)⁺=376.

Example 13N-{(1R,2S)-2-[(hydroxyamino)carbonyl]cyclopentyl}-3′,5′-dimethyl[1,1′-biphenyl]-4-carboxamide

-   (13a) Using procedures analogous to those described for reactions    (1a)-(1d), 4-carbomethoxyphenylboronic acid (0.72 g, 2 eq) and    4-bromo-meta-xylene (0.37 g, 2.0 mmol) were reacted to give the    desired hydroxamic acid (22 mg, 14% for 4 steps). MS found:    (M+H)⁺=353.

Example 14N-{(1R,2S)-2-[(hydroxyamino)carbonyl]cyclopentyl}-6-(2-methylphenyl)nicotinamide

-   (14a) Using procedures analogous to those described for reactions    (1a)-(1d), methyl 6-(3-methylphenyl)nicotinate (0.3 g, 1.4 mmol) and    2-methylphenylboronic acid (0.21 g, 1.1 eq) were reacted to give the    desired product (18 mg, 17% for 4 steps). MS found: (M+H)⁺=340.

Example 15N-{(1R,2S)-2-[(hydroxyamino)carbonyl]cyclopentyl}-6-(2-methoxyphenyl)nicotinamide

-   (15a) Using procedures analogous to those described for reactions    (1a)-(1d), methyl 6-(3-methylphenyl)nicotinate (378 mg, 1.75 mmol)    and 2-methoxyphenylboronic acid (292 mg, 1.1 eq) were reacted to    give the desired product (10 mg, 6% for 4 steps). MS found:    (M+H)⁺=356.

Example 16(3S,4S)-N-hydroxy-1-isopropyl-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-3-pyrrolidinecarboxamide

-   (16a) A solution of benzyl methyl maleate (15.0 g, 68.2 mmol) in    benzene (1 L) at reflux was treated with a mixture of glycine (8.3    g, 2 eq) and para-formaldehyde (8.3 g, 4 eq) portionwise over 1 h.    The mixture was heated at reflux for 2 h further. The mixture was    filtered through a plug of silica and concentrated providing the    desired amine (19.3 g, 100%). MS found: (M+H)⁺=264.-   (16b) The amine from reaction (16a) (7.3 g, 27.5 mmol) in    N,N-dimethylformamide was treated with di-t-butyl dicarbonate (9.0    g, 1.5 eq), triethylamine (5.8 mL, 1.5 eq), and hydroxylamine    hydrochloride (0.2 g, 0.1 eq) and stirred for 17 h. The mixture was    partitioned between water and ether (100 mL each) and the aqueous    layer further extracted with ether (100 mL). The combined ether    layers were washed with water and brine (100 mL each) dried (MgSO₄)    and concentrated. Silica gel column chromatography (ethyl    acetate-hexane, 3:2) yielded the desired ester (6.39 g, 64%). MS    found: (M−Bu)=308.-   (16c) The ester from reaction (16b) (8.3 g, 22.9 mmol) in methanol    (100 mL) was treated with 10% palladium hydroxide on carbon (2.28 g,    0.1 eq) and stirred under a balloon of hydrogen for 3.5 h. The    mixture was purged with nitrogen, filtered through a plug of    Celite®, washed with excess methanol, and the filtrate concentrated    providing the desired acid (6.0 g, 96%). MS found: (M+Na)⁺=296.-   (16d) The acid from reaction (16c) (2.73 g, 0.01 mmol) in benzene    (100 mL) was treated with triethylamine (2.1 mL, 1.5 eq) and    diphenylphosphorylazide (2.58 mL, 1.2 eq) and stirred at room    temperature for 1 h. Benzyl alcohol (1.03 mL, 1.0 eq) was added and    the mixture heated to reflux for 1.5 h. The mixture was cooled and    partitioned between ethyl acetate and saturated aqueous NaHCO₃ (100    mL each). The organic layer was washed further with NaHCO₃ and brine    (100 mL each), dried (MgSO₄), and concentrated. Silica gel column    chromatography (ethyl acetate-hexane, 3:2) yielded the desired    carbamate (2.86 g, 76%). MS found: (M+H)⁺=379.-   (16e) The carbamate from reaction (16d) (2.86 g, 7.6 mmol) in    methanol (38 mL) was treated with 10% palladium hydroxide on carbon    (0.53 g, 0.1 eq) and stirred under a balloon of hydrogen for 1.5 h.    The mixture was purged with nitrogen, filtered through a plug of    Celite®, washing with excess methanol, and the filtrate concentrated    providing the desired amine (1.85 g, 100%). MS found: (M−Bu)=189.-   (16f) The amine from reaction (16e) (11 g, 45 mmol) in DMF (225 mL)    was treated with 4-[(2-methyl-4-quinolinyl)methoxy]benzoic acid    (19.8 g, 1.5 eq), BOP reagent (32.1 g, 1.6 eq) and    N,N-diisopropylethylamine (20 mL, 2.5 eq) and stirred for 5 h. The    mixture was partitioned between saturated aqueous NH₄Cl and ethyl    acetate (500 mL each). The aqueous layer was further extracted with    ethyl acetate (3×500 mL). The combined layers were dried (MgSO₄) and    concentrated. Silica gel column chromatography (ethyl acetate)    yielded the desired racemic amide (13 g). Chiral HPLC separation    provided the (3S,4S)-enantiomer (5.5 g, 23%, >98% ee), MS found:    (M+H)⁺=520, and the (3R,4R)-enantiomer (4.5 g, 19%). MS found:    (M+H)⁺=520.-   (16g) The (3S,4S)-enantiomer from reaction (16f) (2.11 g, 4.06 mmol)    in dichloromethane/trifluoracetic acid (1:1, 16 mL) was stirred for    1 h and concentrated. The residue was dissolved in water and    lyophilized to provide the desired amine as the    bis(trifluoroacetate) salt (2.6 g, 100%). MS found: (M+H)⁺=420.-   (16h) The amine from reaction (16g) (699 mg, 1.08 mmol) in    dichloromethane (10 mL) was treated with N,N-diisopropylethylamine    (0.77 mL, 4 eq), acetone (0.16 mL, 2 eq) and stirred at rt for 10    min. Na(OAc)₃BH (0.46 g, 2 eq) was then added and the mixture    stirred for 1 h. The mixture was partitioned between ethyl acetate    and saturated aqueous NaHCO₃ and then further extracted with ethyl    acetate (4×). The organic layers were dried (MgSO₄) and    concentrated. Silica gel column chromatography    (methanol/dichloromethane, 1:4) yielded the desired amine (0.411 g,    89%). MS Found: (M+H)⁺=462.-   (16i) Preparation of hydroxylamine/potassium hydroxide solution: A    solution of potassium hydroxide (2.81 g, 1.5 eq) in methanol (7 mL)    was added to a hot solution of hydroxylamine hydrochloride (2.34 g,    33.7 mmol) in methanol (12 mL). After the mixture was cooled to room    temperature, the precipitate was removed by filtration. The filtrate    was used fresh and assumed hydroxylamine concentration of 1.76 M.    -   The above freshly prepared 1.76 M hydroxylamine solution (7.6        mL, 15 eq) was added to the methyl ester (400 mg, 0.88 mmol)        from reaction (16h) in methanol (9 mL) and stirred at room        temperature for 0.5 h. The mixture was adjusted to pH 7 with 1 N        hydrochloric acid and diluted with brine (50 mL) and extracted        with dichloromethane (5×60 mL). The organic layers were dried        (MgSO₄) and concentrated. Reverse phase HPLC purification        (gradient elution, water/acetonitrile 85-15 to 60-40, 0.1% TFA)        provided the hydroxamic acid (207 mg, 34%). MS found:        (M+H)⁺=463.

Example 17(3S,4S)-1-(2,2-dimethylpropanoyl)-N-hydroxy-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-3-pyrrolidinecarboxamide

-   (17a) The amine from reaction (16g) (270 mg, 0.42 mmol) in    dichloromethane (4 mL) was treated with triethylamine (0.57 mL, 10    eq), trimethylacetyl chloride (0.1 mL, 2 eq) and stirred at rt for    1 h. The mixture was partitioned between ethyl acetate and saturated    aqueous NaHCO₃ and then further extracted with ethyl acetate (4×).    The organic layers were dried (MgSO₄) and concentrated. Silica gel    column chromatography (methanol/dichloromethane, 1:4) yielded the    desired amide (189 mg, 90%). MS Found: (M+H)⁺=504.-   (17b) Using procedures analogous to reaction (16i) the methyl ester    from reaction (17a) (0.3 g, 6.0 mmol) was converted to the desired    hydroxamic acid (107 mg, 30%). MS Found: (M+H)⁺=505.

Example 18 (3S,4S)-N-hydroxy-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-1-(methylsulfonyl)-3-pyrrolidinecarboxamide

-   (18a) The amine from reaction (16g) (206 mg, 0.33 mmol) in    dichloromethane (3.3 mL) was treated with triethylamine (0.5 mL, 10    eq), methanesulfonyl chloride (0.05 mL, 2 eq) and stirred at rt for    1 h. The mixture was partitioned between ethyl acetate and saturated    aqueous NaHCO₃ and then further extracted with ethyl acetate (4×).    The organic layers were dried (MgSO₄) and concentrated. Silica gel    column chromatography (methanol/dichloromethane, 1:4) yielded the    desired amide (128 mg, 57%). MS Found: (M)⁺=498.-   (18b) Using procedures analogous to reaction (16i), the methyl ester    from reaction (18a) (224 mg, 4.5 mmol) was converted to the desired    hydroxamic acid (104 mg, 37%). MS Found: (M+H)⁺=499

Example 19(3S,4S)-N-hydroxy-1-methyl-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-3-pyrrolidinecarboxamide

-   (19a) Using procedures analogous to those described for example    (16h-i), the amine from reaction (16g) (0.324 g, 0.5 mmol) and    formaldehyde (37%, 0.06 mL, 1.5 eq) were converted to the desired    hydroxamic acid (155 mg, 25% 2 steps). MS Found: (M+H)⁺=435.

Example 20 tert-butyl(3S,4S)-3-[(hydroxyamino)carbonyl]-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-1-pyrrolidinecarboxylate

-   (20a) 1,3-Pyrrolidinedicarboxylic acid, 4-oxo-1-(1,1-dimethylethyl)    3-methyl ester (2.45 g, 10.1 mmol) in benzene (50 mL) was treated    with (R)-alpha-methylbenzyl amine (1.7 mL, 1.3 eq) and Yttrbium    triflate (0.12 g, 0.02 eq) and heated to reflux for 3 h.    Concentration, followed by silica gel column chromatography (ethyl    acetate/hexane, 1:4) yielded the desired amine (2.49 g, 67%). MS    Found: (M+H)⁺=347.-   (20b) The product from reaction (20a) (1.0 g, 2.9 mmol) in    acetonitrile/acetic acid (1:1, 5.8 mL) was treated with NaBH₃CN and    stirred for 0.5 h. The mixture was quenched with NaHCO₃ (aq) until    pH 7 and extracted with ethyl acetate (3×100 mL). The combined    layers were dried (MgSO₄) and concentrated. Silica gel column    chromatography (ethyl acetate/hexane, 3:1) yielded the (3S,4S) amine    (59.4 mg, 6%), MS Found: (M)⁺=349, the (3S,4R) amine (415 mg, 41%    mmol) MS Found: (M)⁺=349 and the (3R,4S) amine (246 mg, 24%) MS    Found: (M)⁺=349.-   (20c) The (3S,4S) amine from reaction (20b) (59.4 mg, 0.17 mmol) in    methanol/water/acetic acid (10:1:0.25, 1 mL) was treated with 10%    palladium hydroxide on carbon (12 mg, 0.1 eq) and stirred under a    balloon of hydrogen for 1.5 h. The mixture was purged with nitrogen,    filtered through a plug of Celite®, washing with excess methanol and    the filtrate concentrated providing the crude amine (37.9 mg) that    was used without purification. In an analogous reaction to (1f) the    crude amine was converted to the desired amide (64.5 mg, 72% two    steps). MS Found: (M+H)⁺=520.-   (20d) Using procedures analogous to reaction (16i), the methyl ester    from reaction (20c) (60 mg, 0.12 mmol) was converted to the desired    hydroxamic acid (42.4 mg, 58%). MS Found: (M+H)⁺=521.

Example 21(3S,4S)-N-hydroxy-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-3-pyrrolidinecarboxamide

-   (21a) In an analogous procedure to (16g) the product from reaction    (20d) (12 mg, 0.02 mmol) was converted to the desired amine (8.7 mg,    72%). MS Found: (M+H)⁺=421.

Example 22 tert-butyl4-[cis-3-[(hydroxyamino)carbonyl]-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)pyrrolidinyl]-1-piperidinecarboxylate

-   (22a) In an analogous procedure to (16g) the racemic product from    reaction (16h-16i) (0.25 g, 0.4 mmol) and Boc-4-piperidone (1.15 mg,    1.5 eq) was converted to the desired hydroxamic acid (49.4 mg, 18% 2    steps). MS Found: (M+H)⁺=604.

Example 23cis-N-hydroxy-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-1-(4-piperidinyl)-3-pyrrolidinecarboxamide

-   (23a) In an analogous procedure to (16g) the product from reaction    (22a) (25.2 mg, 0.03 mmol) was converted to the desired amine (21.4    mg, 82%). MS Found: (M+H)⁺=504.

Example 24cis-1-[3-[(1,1-dimethylethoxy)carbonyl]pyrollidinyl]-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-pyrollidinecarboxamidebis(trifluoroacetate)

-   (24a) In an analogous procedure to (1g) the racemic product from    reaction (16h-16i) (0.25 g, 0.4 mmol) and Boc-3-pyrollidinone (107    mg, 1.5 eq) was converted to the desired hydroxamic acid (73.1 mg,    26% 2 steps). MS Found: (M+H)⁺=590.

Example 25cis-N-hydroxy-1-[3-pyrollidinyl]-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-pyrollidinecarboxamidetris(trifluoroacetate)

-   (25a) In an analogous procedure to (16g), the product from reaction    (24a) (31 mg, 0.04 mmol) was converted to the title compound (27.0    mg, 86%). MS Found: (M+H)⁺=490.

Example 26 tert-butyl(3R,4R)-3-[(hydroxyamino)carbonyl]-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-1-pyrrolidinecarboxylate

-   (26a) In an analogous procedure to (16h), the (3R,4R)-enantiomer    from reaction (16f) (0.2 g, 0.4 mmol) was converted to the desired    hydroxamic acid (18.3 mg, 7%). MS Found: (M+H)⁺=521.

Example 27 tert-butyl(3S,4R)-3-[(hydroxyamino)carbonyl]-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-1-pyrrolidinecarboxylate

-   (27a) In an analogous procedure to (20c-d), the (3S,4R)-amine from    reaction (20b) (0.4 g, 1.2 mmol) was converted to the hydroxamic    acid (53.6 mg, 20%, 2 steps). MS Found: (M+H)⁺=521.

Example 28(3S,4R)-N-hydroxy-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-3-pyrrolidinecarboxamide

-   (28a) In an analogous procedure to (16g), the product from reaction    (27a) (11 mg, 0.02 mmol) was converted to the desired amine (5 mg,    45%). MS Found: (M+H)⁺=421.

Example 29 tert-butyl(3R,4S)-3-[(hydroxyamino)carbonyl]-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-1-pyrrolidinecarboxylate

-   (29a) In an analogous procedure to (20c-d), the (3R,4S)-amine from    reaction (20b) (0.2 g, 0.6 mmol) was converted to the hydroxamic    acid (132 mg, 59%, 2 steps). MS Found: (M+H)⁺=521.

Example 30(3R,4S)-N-hydroxy-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-3-pyrrolidinecarboxamide

-   (30a) In an analogous procedure to (16g), the product from reaction    (29a) (10 mg, 0.02 mmol) was converted to the desired amine (9.8 mg,    98%). MS Found: (M+H)⁺=421.

Example 31N-{(1R,2S)-2-[(hydroxyamino)carbonyl]cyclopentyl}-4-(4-pyridinyl)benzamidetrifluoroacetate

-   (31a) Tetrakis(triphenylphosphine)palladium(0) (0.64 g, 0.1 eq) was    added to a mixture of 4-methoxycarbonylphenyl-boronic acid (2.0 g,    11.1 mmol), 4-bromopyridine hydrochloride (1.03 g, 1 eq), sodium    carbonate (2 M, 2 eq), methanol (10 mL) and benzene (10 mL) at rt.    The mixture was heated to 70° C. for 2 h and cooled to rt. The    mixture was diluted with ethyl acetate and saturated aqueous sodium    bicarbonate (100 mL ea).-   The organic layers were washed with water and brine (100 mL each),    dried (MgSO₄), and concentrated. Silica gel column chromatography    (ethyl acetate-hexane, 1:1) yielded the desired product (1.0 g,    85%). MS found: (M+H)⁺=214.-   (31b) The ester (1.0 mg, 4.7 mmol) from reaction (31a), lithium    hydroxide (1 M, 10 eq) and methanol (50 mL) were stirred at 40° C.    for 2 h. The pH of the mixture was adjusted to pH=7 with 1 N HCl and    then extracted with ethyl acetate (2×100 mL), dried (MgSO₄), and    concentrated, yielding the desired acid (400 mg, 43%). MS found:    (M+H)⁺=200.-   (31c) BOP reagent (266 mg, 1.2 eq) was added to a mixture of    (1R,2S)-2-carbomethoxycyclopentyl amine hydrochloride (90 mg, 0.50    mmol), the carboxylic acid (100 mg, 1 eq) from reaction (31b),    N,N-diisopropylethylamine (0.22 mL, 2.5 eq) and    N,N-dimethylformamide (1 mL) at rt. After 2.5 h at rt, saturated    aqueous ammonium chloride (25 mL) was added and the mixture    extracted with ethyl acetate (2×20 mL). The mixture was washed with    water (10 mL), brine (10 mL), dried (MgSO₄), and concentrated.    Silica gel column chromatography (ethyl acetate) yielded the desired    product (113 mg, 69%). MS found: (M+H)⁺=325.-   (31d) Freshly prepared 1.76 M hydroxylamine solution (8 mL, 20 eq)    was added to the methyl ester (233 mg, 0.7 mmol) from reaction (31c)    in methanol (1 mL) and stirred at room temperature for 0.5 h. The    mixture was adjusted to pH 7 with 1 N hydrochloric acid and diluted    with ethyl acetate (10 mL). The organic layer was washed with brine    (5 mL), dried (MgSO₄), and concentrated. Reverse phase HPLC    purification (gradient elution, water/acetonitrile 85-15 to 10-90)    provided the desired hydroxamic acid (83 mg, 35%). MS found:    (M+H)⁺=326.

Example 32(3S,4S)-1-(1,1-dimethyl-2-propynyl)-N-hydroxy-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-3-pyrrolidinecarboxamidebis(trifluoroacetate)

-   (32a) The amine from reaction (16g) (224 mg, 0.34 mmol) in    dichloromethane (3 mL) was treated with triethylamine (0.24 mL, 5    eq), 3,3-dimethylpropargyl chloride (0.05 mL, 1.2 eq), water (1.5    mL), catalytic copper(I) chloride and catalytic copper turnings and    stirred at rt for 1 h. The mixture was diluted with dichloromethane    and washed with water (50 mL each), dried (MgSO₄) and concentrated.    Silica gel column chromatography (methanol/dichloromethane, 1:4)    yielded the desired amine (150 mg, 89%). MS Found: (M+H)⁺=486.-   (32b) In an analogous procedure to (16i) the ester from reaction    (32a) (150 mg, 0.3 mmol) was converted to the desired hydroxamic    acid (8.4 mg, 6%). MS Found: (M+H)⁺=487.

Example 33(3S,4S)-N-hydroxy-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-1-(2-propynyl)-3-pyrrolidinecarboxamidebis(trifluoroacetate)

-   (33a) The amine from reaction (16g) (204 mg, 0.32 mmol) in    dichloromethane (3 mL) was treated with triethylamine (0.18 mL, 4    eq), propargyl bromide (80% wt. in toluene, 0.04 mL, 1.1 eq) and    stirred for 4 h. The mixture was partitioned between ethyl acetate    and water (25 mL, ea) and the organic layer dried (MgSO₄), filtered    and concentrated. Silica gel column chromatography    (methanol/dichloromethane, 1:4) yielded the desired amine (38 mg,    26%). MS Found: (M+H)⁺=458.-   (33b) In an analogous procedure to (16i), the ester from reaction    (33a) (38 mg, 0.08 mmol) was converted to the desired hydroxamic    acid (5 mg, 13%). MS Found: (M+H)⁺=459.

Example 34(3S,4S)-1-allyl-N-hydroxy-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-3-pyrrolidinecarboxamidebis(trifluoroacetate)

-   (34a) Using analogous procedures to (33a-b), the amine from reaction    (16g) (250 mg, 0.39 mmol) and allyl bromide (2 eq) was converted to    the desired amine and then to the desired hydroxamate (92 mg, 47% 2    steps). MS Found: (M+H)⁺=461.

Example 35(3S,4S)-N-hydroxy-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-1-propyl-3-pyrrolidinecarboxamidebis(trifluoroacetate)

-   (35a) Using analogous procedures to (16h-i), the amine from reaction    (16g) (250 mg, 0.39 mmol) and propanal (2 eq) was converted to the    desired amine and then to the desired hydroxamic acid (38 mg, 22% 2    steps). MS Found: (M+H)⁺=463.

Example 36(3S,4S)-N-hydroxy-1-(2-methyl-2-propenyl)-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-3-pyrrolidinecarboxamidebis(trifluoroacetate)

-   (36a) Using analogous procedures to (33a), the amine from reaction    (16g) (224 mg, 0.35 mmol) and 1-bromo-2-methyl propene (1.1 eq) was    converted to the desired ester (110 mg, 67%). MS Found: (M+H)⁺=474.-   (36b) Preparation of hydroxylamine/sodium methoxide solution:    hydroxylamine hydrochloride (2.4 g, 34.5 mmol) and MeOH (9 mL) were    heated to 55° C. Sodium methoxide (25% wt in MeOH, 11.85 mL, 1.5 eq)    was added, the mixture stirred at 55° C. for 5 minutes and cooled to    room temperature then 0° C. Filtration afforded a clear solution    assumed to be ca. 1.64 M. The solution is prepared and used fresh.-   A solution of 1.64 M hydroxylamine solution (3 mL, 20 eq) was added    to the amine from reaction (36a) (110 mg, 0.45 mmol) in MeOH (3 mL)    then stirred for 1 h. The mixture was adjusted to pH 7 with 1 N    hydrochloric acid (3 mL). Reverse phase HPLC purification (gradient    elution, water/acetonitrile 85-15 to 60-40, 0.1% TFA) provided the    hydroxamic acid (67 mg, 25%, 2 steps). MS Found: (M+H)⁺=475.

Example 37(3S,4S)-1-(1,1-dimethyl-2-propenyl)-N-hydroxy-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-3-pyrrolidinecarboxamidebis(trifluoroacetate)

-   (37a) The amine from reaction (32a) (268 mg, 0.55 mmol) was treated    with 5% Pd/BaSO₄ (0.1 eq) in methanol (5.5 mL) and stirred under a    balloon of hydrogen. The catalyst was removed by filtration and the    mixture concentrated. Silica gel column chromatography    (methanol/dichloromethane, 1:4) yielded the desired olefin (150 mg,    56%) MS Found: (M+H)⁺=488.-   (37b) In an analogous procedure to (16i) the ester from reaction    (37a) (106 mg, 0.2 mmol) was converted to the desired hydroxamic    acid (50 mg, 32%). MS Found: (M+H)⁺=489.

Example 38(3S,4S)-N-hydroxy-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-1-tert-pentyl-3-pyrrolidinecarboxamidebis(trifluoroacetate)

-   (38a) The amine from reaction (37a) (61 mg, 0.13 mmol) was treated    with 5% Rh/C (0.1 eq) in methanol (1.3 mL) and stirred under a    balloon of hydrogen. The catalyst was removed by filtration and the    mixture concentrated. Silica gel column chromatography    (methanol/dichloromethane, 1:4) yielded the desired amine (37 mg,    60%) MS Found: (M+H)⁺=490.-   (38b) In an analogous procedure to (16i), the ester from reaction    (38a) (37 mg, 0.08 mmol) was converted to the desired hydroxamic    acid (14 mg, 25%). MS Found: (M+H)⁺=491.

Example 39(3S,4S)-N-hydroxy-1-isopentyl-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-3-pyrrolidinecarboxamidebis(trifluoroacetate)

-   (39a) Using analogous procedures to (16h and 36b), the amine from    reaction (16g) (102 mg, 0.16 mmol) and isovaleraldehyde (3 eq) were    converted to the desired amine and then to the desired hydroxamic    acid (65 mg, 58% 2 steps). MS Found: (M+H)⁺=491.

Example 40(3S,4S)-N-hydroxy-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-1-neopentyl-3-pyrrolidinecarboxamidebis(trifluoroacetate)

-   (40a) Using analogous procedures to (16h and 36b), the amine from    reaction (16g) (60 mg, 0.1 mmol) and pivaldehyde (3 eq) was    converted to the desired amine and then to the desired hydroxamic    acid (44 mg, 64% 2 steps). MS Found: (M+H)⁺=491.

Example 41(3S,4S)-1-butyl-N-hydroxy-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-3-pyrrolidinecarboxamidebis(trifluoroacetate)

-   (41a) Using analogous procedures to (16h and 36b), the amine from    reaction (16g) (120 mg, 0.19 mmol) and butyraldehyde (2 eq) were    converted to the desired amine and then to the desired hydroxamic    acid (20 mg, 15% 2 steps). MS Found: (M+H)⁺=477.

Example 42(3S,4S)-1-(3-butenyl)-N-hydroxy-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-3-pyrrolidinecarboxamidebis(trifluoroacetate)

-   (42a) Using analogous procedures to (33a and 36b), the amine from    reaction (16g) (216 mg, 0.33 mmol) and 4-bromo-1-butene (2 eq) were    converted to the desired amine and then to the desired hydroxamic    acid (68 mg, 30% 2 steps). MS Found: (M+H)⁺=475.

Example 43(3S,4S)-1-(2-butynyl)-N-hydroxy-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-3-pyrrolidinecarboxamidebis(trifluoroacetate)

-   (43a) Using analogous procedures to (33a and 36b), the amine from    reaction (16g) (140 mg, 0.22 mmol) and 1-bromo-2-butyne (1.2 eq)    were converted to the desired amine and then to the desired    hydroxamic acid (50 mg, 32% 2 steps). MS Found: (M+H)⁺=473.

Example 44(3S,4S)-1-(2-furylmethyl)-N-hydroxy-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-3-pyrrolidinecarboxamidebis(trifluoroacetate)

-   (44a) Using analogous procedures to (16h and 36b), the amine from    reaction (16g) (202 mg, 0.48 mmol) and furfural (1.5 eq) were    converted to the desired amine and then to the desired hydroxamic    acid (110 mg, 32% 2 steps). MS Found: (M+H)⁺=501.

Example 45(3S,4S)-N-hydroxy-1-[(5-methyl-2-furyl)methyl]-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-3-pyrrolidinecarboxamidebis(trifluoroacetate)

-   (45a) Using analogous procedures to (16h and 36b), the amine from    reaction (16g) (223 mg, 0.53 mmol) and 5-methyl-furfural (1.5 eq)    were converted to the desired amine and then to the desired    hydroxamic acid (131 mg, 34% 2 steps). MS Found: (M+H)⁺=515.

Example 46(3R,4S)-N-hydroxy-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)tetrahydro-3-furancarboxamidetrifluoroacetate

-   (46a) Sodium hydride (60% dispersion in mineral oil) (5.28 g, 1.1    eq) in ether (120 mL) was treated with methyl glycolate (10.8 g, 120    mmol) dropwise, slowly. The mixture was stirred for 30 min and    cooled to 0° C. Methyl acrylate (12.39 g, 1.2 eq) was added dropwise    to the 0° C. solution. The mixture was stirred for 15 min, warmed to    room temperature and stirred for 1 h. The reaction was cooled to    0° C. and quenched by addition of 5% aqueous H₂SO₄ (200 mL). The    layers were separated and the aqueous layer extracted with ether    (2×250 mL). The combined ether layers were washed with brine (150    mL), dried with MgSO₄, filtered and concentrated. Flash    chromatography (ethyl acetate/hexanes, 75:25) provided the desired    keto-ester (9.9 g, 57%).-   (46b) The keto-ester (3.3 g, 23.0 mmol) from reaction (46a) in    benzene (100 mL) was treated with (R)-alpha-methylbenzyl amine (3.0    mL, 1.02 eq) and yttrbium(III)triflate (0.29 g, 0.02 eq) and heated    to reflux using Dean-Stark conditions for 3 h, then treated with    more (R)-alpha-methylbenzyl amine (0.5 mL) and heated 1 h further.    The solution was cooled to room temperature and washed with water    (50 mL), dried with MgSO₄, filtered and concentrated. Flash    chromatography (ethyl acetate/hexanes, 40:60) provided the desired    enamine (2.7 g, 48%). MS found: (M+H)⁺=248.-   (46c) The enamine (3.43 g, 13.9 mmol) from reaction (46b) in acetic    acid/dichloromethane/acetonitrile (1:1:1, 42 mL) was treated with    NaBH(OAc)₃ and stirred for 5 h. The reaction was cooled to 0° C. and    neutralized with saturated aqueous NaHCO₃ and extracted with    dichloromethane (3×100 mL), dried (MgSO₄), filtered and    concentrated. Flash chromatography (ethyl acetate/hexanes, 30:70)    provided the desired amine (1.01 g, 29%) as a 3:1 mixture of    diastereomers. MS found: (M+H)⁺=250.-   (46d) A mixture of the amine (838 mg, 3.38 mmol) from reaction    (46c), 20% palladium hydroxide on carbon (240 mg, 0.1 eq) in    methanol was shaken on a Parr apparatus under 50 psi of hydrogen for    2 h. The mixture was filtered and concentrated to provide the amine    (495 mg, 100%). MS found: (M+H)⁺=146.-   (46e) A mixture of the amine (274 mg, 1.89 mmol) from reaction (46d)    in DMF (10 mL) was treated with    4-[(2-methyl-4-quinolinyl)methoxy]benzoic acid (691 mg, 1.25 eq),    BOP reagent (1.23 g, 1.5 eq), N,N-diisopropylethylamine (1.0 mL, 3.0    eq) and stirred for 5 h. The mixture was partitioned between    saturated aqueous NH4Cl and ethyl acetate (25 mL each). The aqueous    layer was further extracted with ethyl acetate (3×50 mL). The    combined layers were dried (MgSO₄) and concentrated. Silica gel    column chromatography (gradient elution: ethyl acetate to    methanol/ethyl acetate 1:10) yielded the desired amide (600 mg,    76%). MS found (M+H)⁺=421. Analytical chiral HPLC (Chiracel OD    column, 1:1 hexane/ethanol, 0.75 mL/min, 254 nm) revealed a 77:23    mixture of enantiomers, which were separated on preparative scale    (Chiracel OD column, 98:2 methanol/water) providing the faster    running isomer (3S,4R)-enantiomer (120 mg, 15%, >98% ee)and the    slower running (3R,4S)-enantiomer (440 g, 55%, >98% ee).-   (46f) Using conditions similar to those described for reaction    (36b), the slower running (3R,4S) isomer (130 mg, 0.3 mmol) was    converted to the desired hydroxamic acid (108 mg, 65%). MS Found:    (M+H)⁺=422.

Example 47(3S,4R)-N-hydroxy-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)tetrahydro-3-furancarboxamidetrifluoroacetate

-   (47a) Using conditions similar to those described for reaction    (36b), the faster running (3S,4R) isomer (38 mg, 0.09 mmol) was    converted to the desired hydroxamic acid (45 mg, 92%). MS Found:    (M+H)⁺=422.

Example 48(3S,4S)-N-hydroxy-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-1-(1,3-thiazol-2-ylmethyl)-3-pyrrolidinecarboxamidebis(trifluoroacetate)

-   (48a) Using analogous procedures to (16h) and (36b), the amine from    reaction (16g) (229 mg, 0.55 mmol) and 2-thiazolecarboxaldehyde (1.5    eq) were converted to the desired amine and then to the desired    hydroxamic acid (186 mg, 46%, 2 steps). MS Found: (M+H)⁺=518.

Example 49(3S,4S)-1-acetyl-N-hydroxy-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-3-pyrrolidinecarboxamidetrifluoracetate

-   (49a) A BIO-RAD Poly-Prep® chromatography column (0.8×4 cm) vessel    was charged with a solution of the free base of the amine from    reaction (16g) (0.1 g, 0.24 mmol) in dichloromethane (4 mL). The    mixture was then treated with PS-DIEA resin (Argonaut Technologies)    (215 mg, 3 eq) followed by acetyl chloride (0.026 mL, 1.5 eq). The    vessel was sealed and rotated on a Labquake® rotisserie    (Barnstead/Thermolyne) for 2 h. PS-Trisamine resin (Argonaut    Technologies) (300 mg, 3 eq) was then added, the vessel sealed and    rotated for 1 h. The reaction mixture was then filtered and the    resins rinsed with dichloromethane (4 mL). The filtrate was    concentrated in a test tube to give the desired amide as a white    solid that was taken on without further purification. MS found:    (M+H)⁺=462.-   (49b) The crude amide from reaction (49a), in a test tube, was    treated with a 1.64M solution of NH₂OH/NaOMe/MeOH, as prepared in    example (36b) (2.9 mL, 20 eq), at 0° C. and warmed to ambient    temperature while agitating on a Vortex (1 h). The mixture was    quenched with 1N HCl (2.9 ml) and the ensuing precipitate filtered    affording a white solid. The product was converted to its TFA salt    by dissolution in 0.2 N TFA (5 mL), filtration through a 0.45μ PTFE    membrane, and freeze-drying yielding the desired hydroxamate as a    white amorphous solid (90.7 mg, 66% yield, 2 steps). MS Found:    (M+H)⁺=463.

Example 50(3S,4S)-N-hydroxy-1-isobutyryl-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-3-pyrrolidinecarboxamidetrifluoracetate

-   (50a) Using procedures analogous to (49a)-(49b), the free base of    the amine from reaction (16g) (0.1 g, 0.24 mmol) and isobutyryl    chloride (0.038 mL, 1.5 eq) were converted to the desired amide and    then to the desired hydroxamic acid (112 mg, 77% yield, 2 steps). MS    Found (M+H)⁺=491.

Example 51(3S,4S)-N-hydroxy-1-(3-methylbutanoyl)-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-3-pyrrolidinecarboxamidetrifluoracetate

-   (51a) Using procedures analogous to (49a)-(49b), the free base of    the amine from reaction (16g) (0.1 g, 0.24 mmol) and    3-methylbutanoyl chloride (0.044 mL, 1.5 eq) were converted to the    desired amide and then to the desired hydroxamic acid (116 mg, 78%    yield, 2 steps). MS Found (M+H)⁺=505.

Example 52(3S,4S)-1-(cyclopropylcarbonyl)-N-hydroxy-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-3-pyrrolidinecarboxamidetrifluoracetate

-   (52a) Using procedures analogous to (49a)-(49b), the free base of    the amine from reaction (16g) (0.1 g, 0.24 mmol) and    cyclopropanecarbonyl chloride (0.033 mL, 1.5 eq) were converted to    the desired amide and then to the desired hydroxamic acid (40 mg,    28% yield, 2 steps). MS Found (M+H)⁺=489

Example 53(3S,4S)-1-(cyclobutylcarbonyl)-N-hydroxy-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-3-pyrrolidinecarboxamidetrifluoracetate

-   (53a) Using procedures analogous to (49a)-(49b), the free base of    the amine from reaction (16g) (0.1 g, 0.24 mmol) and    cyclobutanecarbonyl chloride (0.042 mL, 1.5 eq) were converted to    the desired amide and then to the desired hydroxamic acid (83 mg,    56% yield, 2 steps). MS Found (M+H)⁺=503.

Example 54(3S,4S)-N-hydroxy-1-(methoxyacetyl)-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-3-pyrrolidinecarboxamidetrifluoracetate

-   (54a) Using procedures analogous to (49a)-(49b), the free base of    the amine from reaction (16g) (0.1 g, 0.24 mmol) and methoxyacetyl    chloride (0.033 mL, 1.5 eq) were converted to the desired amide and    then to the desired hydroxamic acid (85 mg, 59% yield, 2 steps). MS    Found (M+H)⁺=493.

Example 55(3S,4S)-1-(2-furoyl)-N-hydroxy-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-3-pyrrolidinecarboxamidetrifluoracetate

-   (55a) Using procedures analogous to (49a)-(49b), the free base of    the amine from reaction (16g) (0.1 g, 0.24 mmol) and 2-furoyl    chloride (0.036 mL, 1.5 eq) were converted to the desired amide and    then to the desired hydroxamic acid (75 mg, 50% yield, 2 steps). MS    Found (M+H)⁺=515.

Example 56(3S,4S)-N-hydroxy-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-1-(2-thienylcarbonyl)-3-pyrrolidinecarboxamidetrifluoracetate

-   (56a) Using procedures analogous to (49a)-(49b), the free base of    the amine from reaction (16g) (0.1 g, 0.24 mmol) and    2-thienylcarbonyl chloride (0.039 mL, 1.5 eq) were converted to the    desired amide and then to the desired hydroxamic acid (70 mg, 46%    yield, 2 steps). MS Found (M+H)⁺=531.

Example 57(3S,4S)-N-hydroxy-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-1-propionyl-3-pyrrolidinecarboxamidetrifluoracetate

-   (57a) Using procedures analogous to (49a)-(49b), the free base of    the amine from reaction (16g) (0.1 g, 0.24 mmol) and propionyl    chloride (0.031, 1.5 eq) were converted to the desired amide and    then to the desired hydroxamic acid (71 mg, 51% yield, 2 steps). MS    Found (M+H)⁺=477.

Example 58(3R,4S)-4-{[4-(2-butynyloxy)benzoyl]amino}-N-hydroxy-tetrahydro-3-furancarboxamide

-   (58a) Using procedures analogous to (1c) and (16i) the amine from    reaction (46d) (31 mg, 0.21 mmol, 52% ee) and (49 mg, 1.2 eq) were    converted the amide and then hydroxamic acid (22 mg, 33%). MS Found    (M+H)⁺=319.

Example 59N-{(1R,2S)-2-[(hydroxyamino)carbonyl]-4-oxocyclopentyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamidetrifluoroacetate

-   (59a) 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride    (73.0 g, 1.5 eq) was added to a mixture of (1S,2R)-1-methyl    cis-1,2,3,6-tetrahydrophthalate (46.8 g, 254.2 mmol), benzyl alcohol    (30.2 g, 1.1 eq) and 4-dimethylaminopyridine (3.0 g, 0.1 eq) in    dichloromethane (470 mL) at 0° C. and let warm to room temperature.    After 3 h, the solution was cooled to 0° C. and 1N HCl (300 mL) was    added. The mixture was extracted with dichloromethene (2×300 mL).    The organic layer was washed successively with brine (200 mL), dried    (MgSO₄) and concentrated. 70 g of crude product was obtained and    purified by silica gel column chromatography (ethyl acetate-hexane    (1:10). The desired compound was obtained as colorless oil (68.8 g,    99%). MS found: (M+H)⁺=275.-   (59b) The olefin from reaction (59a) (68.8 g, 251 mmol) was added    dropwise to a solution of potassium permanganate (125 g, 3.2 eq) in    water (400 mL) at 0° C. After 20 min stirring at 0° C., TLC showed    the presence of starting olefin. Another portion of water (400 mL)    and potassium permanganate (125 g) were added. After 20 min the    reaction was complete (by TLC). Sulfur dioxide was bubbled through    the mixture at 0° C. until the color of the solution turned pink    from purple (2 h). The mixture was filtered and the filtrate was    acidified by adding concentrated HCl to pH=1. The reaction was    extracted with ethyl acetate (5×500 mL) and the combined organic    layers were dried over sodium sulfate. After filtration and    concentration, the target diacid was obtained (74 g, 87% yield) and    taken on without further purification. MS found: MS found:    (M+H)⁺=339.-   (59c) Sodium acetate (11.4 g, 138 mmol) was added to a solution of    the dicarboxylic acid from reaction (59b) (57 g, 169 mmol) in acetic    anhydride (43 g, 421 mmol) at rt. The reaction was refluxed for 2 h,    and cooled to rt. Acetic anhydride was removed by rotary evaporation    under reduced pressure. Water (600 mL) was added and the residue was    extracted with ethyl acetate (1 L×2). The combined organic layers    were dried over MgSO₄. After filtration and concentration, the crude    ketone was obtained. Purification by silica gel column    chromatography (Ethyl acetate 33% in hexane) furnished the target    ketone (21 g, 45% yield). MS found: (M)⁺=276.-   (59d) The ketone from reaction (59c) (7 g, 25.3 mmol), ethylene    glycol (15.7 g, 253.3 mmol) and p-toluenesulfonic acid monohydrate    (481 mg, 2.5 mmol) were refluxed in benzene (507 mL) using    Dean-Stark conditions for 1 h. After cooling, the reaction was    quenched with saturated sodium bicarbonate solution (80 mL) and    extracted with ethyl acetate (2×100 mL). The combined organic layers    were washed with brine (80 mL), dried over magnesium sulfate,    filtered and concentrated. The purification by silica gel column    chromatography (Ethyl acetate 33% in hexane) furnished the target    ketal (7.8 g, 97% yield). MS found: (M+H)⁺=321.-   (59e) The ketal from reaction (59d) (7.1 g, 22.3 mmol) and palladium    hydroxide on carbon (20 wt %, 780 mg, 0.1 eq) were stirred in ethyl    acetate (11 mL) under hydrogen (balloon) at rt for 45 min. After    filtration and concentration, the target carboxylic acid (5.1 g, 99%    yield) was obtained. MS found: (M+H)⁺=231.-   (59f) To a solution of the carboxylic acid from reaction (59e) (447    mg, 1.9 mmol) in acetone was added triethylamine (393 mg, 3.9 mmol)    and ethyl chloroformate (316 mg, 2.9 mmol) at −25° C. under    nitrogen. After stirring at rt for 10 min, sodium azide (316 mg, 4.9    mmol) dissolved in water (0.5 mL) was added to the mixture at    −10° C. The reaction was stirred at rt for 1 h, and quenched with    water (20 mL). It was extracted with CH₂Cl₂ (2×50 mL), washed with    brine (30 mL), dried over MgSO₄, filtered, and concentrated. The    crude azide was dissolved in benzene (2.6 mL) and refluxed for 1 h.    -   Benzyl alcohol (210 mg, 1.9 mmol) and p-toluenesulfonic acid (18        mg, 0.1 mmol) were added and the mixture was refluxed for 1 h.        After cooling to rt, the reaction was quenched with water and        extracted with CH₂Cl₂ (2×50 mL) The combined organic layer was        washed with brine (50 mL), dried over MgSO₄, filtered, and        concentrated. The crude was purified by silica gel column        chromatography (33%EtOAc in hexane). The target amide (393 mg,        60% yield) was obtained. MS found: (M+H)⁺=236.-   (59g) The Cbz protected amine from reaction (59f) (3.8 g, 11.3    mmol), triethylamine (1.1 g, 11.3 mmol) and palladium hydrooxide on    carbon (20 wt %, 400 mg, 0.56 mmol) were stirred in EtOAc (57 mL)    under hydrogen (50 psi) at rt for 2 h. After filtration and    concentration, the target amine was obtained (2.2 g, 96% yield). MS    found: (M+H)⁺=202.-   (59h) To the solution of the amine from reaction (59g) (2.2 g, 11.3    mmol), 4-[(2-methyl-4-quinolinyl)methoxy]benzoic acid (3.49 g, 11.9    mmol) and diisopropylethylamine (3.7 g, 28.3 mmol) in DMF (57 mL)    was added BOP reagent (6 g, 13.6 mmol) at 0° C. After stirring at rt    for 3 h, the reaction was quenched with NH₄Cl (100 mL) at 0° C.,    extracted with EtOAc (300 mL×2), washed with brine (100 mL), dried    over Na₂SO₄, filtered and concentrated. The crude (14 g) was    purified by silica gel column chromatography (Gradient elution ethyl    acetate/hexane, 1:1 to ethyl acetate) to give the target compound    amide (5.4 g, 99% yield). MS found: (M+H)⁺=477.-   (59i) Using conditions analogous to (36b) and the ester from    reaction (59h) (300 mg, 0.63 mmol) was converted to the desired    hydroxamic acid (220 mg, 73% yield. (M+H)⁺=478.-   (59j) The compound from reaction (59i) (24 mg, 0.0511 mmol) was    dissolved in TFA (5 mL). After 10 min stirring at rt, TFA was    evaporated. The crude was dissolved in DMSO and purified by HPLC.    The TFA salt of target hydroxyamine compound was obtained (28 mg,    99% yield). MS found: (M+H)⁺=434.

Example 60N-{(1R,2S,4R)-4-hydroxy-2-[(hydroxyamino)carbonyl]cyclopentyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamidetrifluoracetate

-   (60a) The compound from reaction (59h) (47 mg, 0.1 mmol) in THF (0.4    mL) was treated with HCl (3N solution, 0.4 mL) at rt for 3 h. The    reaction was quenched with saturated NaHCO3 to basic solution at    0° C. The mixture was extracted with ethyl acetate (20 mL×2), washed    with brine (10 mL), dried over Na₂SO₄, filtered, and concentrated.    Silica gel chromatography (dichloromethane/methanol, 20:1) provided    the desired ketone (25 mg, 59% yield). MS found: (M+H)⁺=231-   (60b) To a solution of the ketone from reaction (60a) (520 mg, 1.2    mmol) in MeOH (120 mL) was added NaBH₄ at 0° C. The reaction was    stirred at rt for 20 min. MeOH was evaporated. The reaction was    diluted with ethyl acetate and quenched with saturated aqueous NH₄Cl    at 0° C. White solid was filtered and the filtrate was extracted    with EtOAc (200 mL×2), dried over Na₂SO₄, filtered and concentrated.    The crude alcohol was purified by silica gel column chromatography    (5% MeOH in CH₂Cl₂) to give two diastereomers. Major diastereomer    (380 mg, 73% yield) and minor one (95 mg, 18%) were obtained. MS    found: (M+H)⁺=435.-   (60c) Using conditions analogous to (36b) and the major diastereomer    from reaction (60b) (50 mg, 0.12 mmol) was converted to the desired    hydroxamic acid (29 mg, 46% yield. (M+H)⁺=436.

Example 61N-{(1R,2S,4S)-4-hydroxy-2-[(hydroxyamino)carbonyl]cyclopentyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamidetrifluoracetate

-   (61a) Using conditions analogous to (36b) the minor diastereomer    from reaction (60b) (50 mg, 0.12 mmol) was converted to the desired    hydroxamic acid (57 mg, 91% yield. (M+H)⁺=436.

Example 62(3S,4S)-N-hydroxy-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-1-tetrahydro-2H-pyran-4-yl-3-pyrrolidinecarboxamidebis(trifluoroacetate)

-   (62a) Using analogous procedures to (16h and 36b), the amine from    reaction (16g) (205 mg, 0.49 mmol) and tetrahydro-4H-pyran-4-one    (0.068 mL, 1.5 eq) were converted to the desired amine and then to    the desired hydroxamic acid (100 mg, 28%, 2 steps). MS Found:    (M+H)⁺=505.

Example 63 methyl(3S,4S)-3-[(hydroxyamino)carbonyl]-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-1-pyrrolidinecarboxylatetrifluoroacetate

-   (63a) A BIO-RAD Poly-Prep® chromatography column (0.8×4 cm) vessel    was charged with a solution of the free base of the amine from    reaction (16g) (0.1 g, 0.24 mmol) in dichloromethane (6 mL). The    mixture was then treated with PS-DIEA resin (Argonaut Technologies)    (215 mg, 3 eq) followed by methylchloroformate (0.028 mL, 1.5 eq).    The vessel was sealed and rotated on a Labquake® rotisserie    (Barnstead/Thermolyne) for 6 h. PS-Trisamine resin (Argonaut    Technologies) (300 mg, 3 eq) was then added, the vessel sealed and    rotated for 16 h. The reaction mixture was then filtered and the    resins rinsed with dichloromethane (4 mL). The filtrate was    concentrated in a test tube to give the desired carbamate as a white    solid that was taken on without further purification. MS found:    (M+H)⁺=478.-   (63b) The crude carbamate from reaction (49a), in a test tube, was    treated with a 1.64M solution of NH₂OH/NaOMe/MeOH, as prepared in    example (36b) (2.9 mL, 20 eq), at 0° C. and warmed to ambient    temperature while agitating on a Vortex (1 h). The mixture was    quenched with 1N HCl (2.9 ml) and the ensuing precipitate filtered    affording a white solid. The product was converted to its TFA salt    by dissolution in 0.2 N TFA (5 mL), filtration through a 0.45μ PTFE    membrane, and freeze-drying yielding the desired hydroxamate as a    white amorphous solid (119 mg, 84% yield, 2 steps). MS Found:    (M+H)⁺=479.

Example 64 ethyl(3S,4S)-3-[(hydroxyamino)carbonyl]-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-1-pyrrolidinecarboxylatetrifluoracetate

-   (64a) Using procedures analogous to (63a)-(63b), the free base of    the amine from reaction (16g) (0.1 g, 0.24 mmol) and    ethylchloroformate (0.034 mL, 1.5 eq) were converted to the desired    carbamate and then to the desired hydroxamic acid (136 mg, 94%    yield, 2 steps). MS Found (M+H)⁺=493.

Example 65 propyl(3S,4S)-3-[(hydroxyamino)carbonyl]-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-1-pyrrolidinecarboxylatetrifluoroacetate

-   (65a) Using procedures analogous to (63a)-(63b), the free base of    the amine from reaction (16g) (0.1 g, 0.24 mmol) and    propylchloroformate (0.040 mL, 1.5 eq) were converted to the desired    carbamate and then to the desired hydroxamic acid (134 mg, 90%    yield, 2 steps). MS Found (M+H)⁺=507.

Example 66 allyl(3S,4S)-3-[(hydroxyamino)carbonyl]-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-1-pyrrolidinecarboxylatetrifluoroacetate

-   (66a) Using procedures analogous to (63a)-(63b), the free base of    the amine from reaction (16g) (0.1 g, 0.24 mmol) and    allylchloroformate (0.038 mL, 1.5 eq) were converted to the desired    carbamate and then to the desired hydroxamic acid (122 mg, 82%    yield, 2 steps). MS Found (M+H)⁺=505.

Example 67 isopropyl(3S,4S)-3-[(hydroxyamino)carbonyl]-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-1-pyrrolidinecarboxylatetrifluoroacetate

-   (67a) Using procedures analogous to (63a)-(63b), the free base of    the amine from reaction (16g) (0.1 g, 0.24 mmol) and    isopropylchloroformate (1M in toluene, 0.36 mL, 1.5 eq) were    converted to the desired carbamate and then to the desired    hydroxamic acid (127 mg, 85% yield, 2 steps). MS Found (M+H)⁺=507.

Example 68 2-propynyl(3S,4S)-3-[(hydroxyamino)carbonyl]-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-1-pyrrolidinecarboxylatetrifluoroacetate

-   (68a) Using procedures analogous to (63a)-(63b), the free base of    the amine from reaction (16g) (0.1 g, 0.24 mmol) and    2-propynylchloroformate (0.035 mL, 1.5 eq) were converted to the    desired carbamate and then to the desired hydroxamic acid (88 mg,    60% yield, 2 steps). MS Found (M+H)⁺=503.

Example 69 2-butynyl(3S,4S)-3-[(hydroxyamino)carbonyl]-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-1-pyrrolidinecarboxylatetrifluoroacetate

-   (69a) Using procedures analogous to (63a)-(63b), the free base of    the amine from reaction (16g) (0.1 g, 0.24 mmol) and    2-butynylchloroformate (0.041 mL, 1.5 eq) were converted to the    desired carbamate and then to the desired hydroxamic acid (96 mg,    63% yield, 2 steps). MS Found (M+H)⁺=517.

Example 70 3-butenyl(3S,4S)-3-[(hydroxyamino)carbonyl]-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-1-pyrrolidinecarboxylatetrifluoroacetate

-   (70a) Using procedures analogous to (63a)-(63b), the free base of    the amine from reaction (16g) (0.1 g, 0.24 mmol) and    3-butenylchloroformate (0.045 mL, 1.5 eq) were converted to the    desired carbamate and then to the desired hydroxamic acid (109 mg,    72% yield, 2 steps). MS Found (M+H)⁺=519.

Example 71 benzyl(3S,4S)-3-[(hydroxyamino)carbonyl]-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-1-pyrrolidinecarboxylatetrifluoroacetate

-   (71a) Using procedures analogous to (63a)-(63b), the free base of    the amine from reaction (16g) (0.1 g, 0.24 mmol) and    benzylchloroformate (0.051, 1.5 eq) were converted to the desired    carbamate and then to the desired hydroxamic acid (98 mg, 61% yield,    2 steps). MS Found (M+H)⁺=554.

Example 72N-{(1R,2S)-4-(dimethylamino)-2-[(hydroxyamino)carbonyl]cyclopentyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamidebis(trifluoroacetate

-   (72a) Using procedures analogous to examples (36a) and (36b) the    ketone from example (60a) (50 mg, 0.12 mmol) and dimethyl amine were    converted to the desired amine and then the desired hydroxamic acid    (74 mg, 27% yield). MS found: (M+H)⁺=463

Example 73(3S,4S)-4-{[4-(2-butynyloxy)benzoyl]amino}-N-hydroxy-1-isopropyl-3-pyrrolidinecarboxamide

-   (73a) The amide from reaction (16g) (510 mg, 1.10 mmol) in AcOH (2    mL) and dichloromethane (4 mL) was treated with zinc dust (217 mg, 3    eq)) and stirred for 24 h at ambient temperature. The remaining zinc    was filtered off and the filtrate neutralized with saturated aqueous    NaHCO3 (5 mL) and extracted with ethyl acetate (3×10 mL). The    combined extracts were dried (MgSO₄) and concentrated. Silica gel    chromatography (ethyl acetate) provided the desired phenol (259 mg,    77%). MS Found: (M+H)+307.-   (73b) 2-Butyn-1-ol (105 mg, 1.5 eq)) was treated with    triphenylphosphine (393 mg, 1.5 eq.) and diethylazodicarboxylate    (0.24 mL, 1.5 eq) in benzene (10 mL). The phenol from reaction (73a)    (307 mg, 1.0 mmol) in benzene (5 mL) was added via cannula and the    mixture stirred for 12 h. The mixture was quenched with water (20    mL) and extracted with ethyl acetate (3×30 mL). The combined organic    layers were dries (MgSO₄), filtered and concentrated. Silica gel    chromatography (ethyl acetate) provided the desired ether (200 mg,    45%). MS Found: (M+H)⁺=459.-   (73c) Using procedures analogous to (36b), the ester from reaction    (73b) (200 mg, 0.44 mmol) was converted to the desired hydroxamic    acid (57 mg, 28% yield). MS Found (M+H)⁺=360.

Example 74N-{(1R,2S)-4,4-difluoro-2-[(hydroxyamino)carbonyl]cyclopentyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamidetrifluoroacetate

-   (74a) To a heterogeneous solution of the ketone from example (60a)    (50 mg, 0.12 mmol) in toluene (0.5 mL) was added diethylaminosulfur    trifluoride (47 mg, 0.29 mmol) at 0° C. The reaction was stirred at    rt for 3 days. The mixture was poured into ice water, extracted with    EtOAc (10 mL×2), dried over Na₂SO₄, filtered and concentrated. Crude    60 mg was purified by silica gel column chromatography (EtOAc 90% in    hexane). The target difluoride compound (18 mg, 34% yield) was    obtained. MS found: (M+H)⁺=455.-   (74b) Using conditions analogous to (36b) and the ester from example    (74a) (18 mg, 0.0.04 mmol) was converted to the desired hydroxamic    acid (11 mg, 49% yield. (M+H)⁺=456.

Example 75(3S,4S)-N-hydroxy-1-isopropyl-4-{[4-(2-methylphenoxy)benzoyl]amino}-3-pyrrolidinecarboxamidetrifluoroacetate

-   (75a) Using procedures analogous to (2a) and (36b), The phenol from    reaction (73a) (100 mg, 0.33 mmol) and 2-methylphenylboronic acid    (135 mg, 0.4 mmol) were converted the desired ester and then    hydroxamic acid (23 mg, 41% yield). MS Found: (M+H)⁺=398.

Example 100cis-N-hydroxy-2-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-1-cyclopentanecarboxamidetrifluoroacetate

-   (100a) A mixture of methyl (+/−)-cis-2-aminocyclopentanecarboxylate    hydrochloride (150 mg, 0.83 mmol),    4-(2-methyl-4-quinolinylmethoxy)benzoic acid (250 mg, 1 eq), DIEA    (0.43 mL, 3 eq) and BOP (0.31 g, 1.2 eq) in DMF (4 mL) was stirred    at rt for 2 h. Following addition of sat NH₄Cl, the mixture was    extracted with ethyl acetate. The extracts were washed with sat    NaHCO₃, brine, dried (MgSO₄) and concentrated in vacuo. Silica gel    chromatography (ethyl acetate-hexane, 60:40 then 80:20) provided the    desired amide (330 mg, 95%). MS (M+H)⁺=419.-   (100b) The freshly prepared 1.76 M solution of hydroxylamine (3.0    mL, 9 eq) was added to the ester from (100a) (240 mg, 0.57 mmol) at    rt. After 30 min at this temperature, the mixture was acidified to    pH 5 with 4 N HCl. The desired hydroxamic acid precipitated out and    collected by filtration (146 mg, 61%). The free base was then    converted to the trifluoroacetate salt in quantitative yield by    reaction with TFA. MS found: (M+H)⁺=420.

Example 101trans-N-hydroxy-2-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-1-cyclopentanecarboxamidetrifluoroacetate

-   (101a) The cis-isomer from (100a) (90 mg, 215 mmol) was dissolved in    toluene (10 mL) and heated to reflux for 45 h. The mixture was    filtered through a pad of silica gel and filter pad washed with    EtOAc until free of product. The filtrate was concentrated to give a    1:1 mixture of trans and cis isomers (77.2 mg, 86%). MS found:    (M+H)⁺=419.-   (101b) Following a procedure similar to that used for step (100b),    the title compound was prepared. The two isomers were separated by    reverse phase HPLC on a Vydac C-18 semiprep column eluting an    acetonitrile:water:TFA gradient, to give the trans hydroxamic acid    product (25%). MS (M+H)⁺=420.

Example 102(1S,2R)-N-hydroxy-2-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-1-cyclopentanecarboxamidetrifluoroacetate

-   (102a-b) Following the procedures similar to that used for steps    (100a-b), but using methyl (1S,2R)-2-aminocyclopentanecarboxylate    hydrochloride (Davies, S. G.; Ichihara, O.; Lenoir, I.;    Walters, A. S. J. Chem. Soc. Perkin Trans. 1994, 1411), the title    compound was prepared. The product was purified by reverse phase    HPLC on a Vydac C-18 semiprep column eluting an    acetonitrile:water:TFA gradient, to give the hydroxamic acid    product. MS (M+H)⁺=420.

Example 103(1R,2S)-N-hydroxy-2-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-1-cyclopentanecarboxamidetrifluoroacetate

-   (103a-b) Following the procedures similar to that used for steps    (100a-b), but using methyl (1R,2S)-2-aminocyclopentanecarboxylate    hydrochloride (Davies, S. G.; Ichihara, O.; Lenoir, I.;    Walters, A. S. J. Chem. Soc. Perkin Trans. 1994, 1411), the title    compound was prepared. The product was purified by reverse phase    HPLC on a Vydac C-18 semiprep column eluting an    acetonitrile:water:TFA gradient, to give the hydroxamic acid    product. MS (M+H)⁺=420.

Example 104cis-N-hydroxy-2-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-1-cyclohexanecarboxamidetrifluoroacetate

-   (104a-b) Following the procedures similar to that used for steps    (100a-b), but using (+/−)-cis-2-aminocyclohexanecarboxylate    hydrochloride, the title compound was prepared. The product was    purified by reverse phase HPLC on a Vydac C-18 semiprep column    eluting an acetonitrile:water:TFA gradient, to give the hydroxamic    acid product. MS (M+H)⁺=434.

Example 105trans-N-hydroxy-2-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-1-cyclohexanecarboxamidetrifluoroacetate

-   (105a-b) Following the procedures similar to that used for steps    (101a-b), but using the cyclohexane analogue, the title compound was    prepared. The product was purified by reverse phase HPLC on a Vydac    C-18 semiprep column eluting an acetonitrile:water:TFA gradient, to    give the hydroxamic acid product. MS (M+H)⁺=434.

Example 108trans-1-[[(1,1-dimethylethyl)oxy]carbonyl]-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-pyrrolidinecarboxamidetrifluoroacetate

-   (108a) A solution of benzyl methyl fumarate (26.4 g, 113 mmol) in    toluene (200 mL) was heated to reflux. A suspension of glycine (11.0    g, 1.3 eq) and paraformaldehyde (4.40 g, 1.3 eq) in toluene (50 mL)    was added over 1 h. The mixture was maintained at reflux for 2 h    after completion of addition. Additional amount of para-formaldehyde    (1 eq) and glycine (1 eq) were added. After additional 30 min at    reflux, the mixture was cooled and filtered. The filtrate was    diluted with ethyl acetate (300 mL) and washed with sat Na2CO3 (2×10    mL), brine (10 mL), dried (MgSO₄) and concentrated. The crude    material was used in the next step without purification. MS    (M+H)⁺=278.-   (108b) DIEA (34.8 mL, 1.8 eq) and (BOC)₂O (36.3 mL, 1.5 eq) were    added to a solution of the crude amine from (108a) in CH₂Cl₂ (600    mL) at 0° C. After 2 days at rt, additional amount of DIEA (1 eq)    and (BOC)₂O (1 eq) were added. After a total of 3 days, the mixture    was washed with sat NaHCO₃ (2×20 mL), brine (20 mL), dried (MgSO₄)    and concentrated in vacuo. Silica gel chromatography (ethyl    acetate-hexane, 10:90 then 20:80) provided the desired product (7.60    g, 20% over 2 steps). MS (M+H)⁺=378.-   (108c) A mixture of the benzyl ester from (108b) (7.40 g, 19.6 mmol)    and Pd(OH)₂ on carbon (1.90 g) in methanol (150 mL) was purged with    hydrogen and stirred under balloon pressure hydrogen for 3 h. The    catalyst was removed by filtration and the filtrate was concentrated    to give the desired carboxylic acid (5.64 g, 100%). MS (2M−H)⁻=573.-   (108d) Et₃N (3.7 mL, 1.5 eq) and DPPA (4.6 mL, 1.2 eq) were added to    a solution of the carboxylic acid from (108c) (5.12 g, 17.8 mmol) in    benzene (150 mL). After 2 h at rt, benzyl alcohol (2.2 mL, 1.2 eq)    was added. The mixture was heated to reflux for 1 h, cooled to rt,    washed with sat NaHCO₃ (2×10 mL), brine (10 mL), dried (MgSO₄) and    concentrated in vacuo. Silica gel chromatography (ethyl    acetate-hexane, 20:80 then 30:70) provided the desired product (4.50    g, 64%). MS (M+H)⁺=393.-   (108e) A mixture of the Cbz-protected intermediate from (108d) (2.30    g, 5.86 mmol) and Pd on carbon (0.60 g) in methanol (100 mL) was    purged with hydrogen and stirred under balloon pressure hydrogen for    2 h. The catalyst was removed by filtration and the filtrate was    concentrated to give the desired amine (1.52 g, 100%). MS    (2M+H)⁺=517.-   (108f) Following the procedures similar to that used for step    (100a), but using the amine from (108e) (1.35 g, 523 mmol), the    amide was prepared. Silica gel chromatography (ethyl acetate-hexane,    50:50 then 60:40) provided the desired product (2.70 g, 85%). MS    (M+H)⁺=534.-   (108g) Following the procedures similar to that used for step    (100b), the ester from (108f) (165 mg, 260 mmol) was converted to    the title compound. The product was purified by reverse phase HPLC    on a Vydac C-18 semiprep column eluting an acetonitrile:water:TFA    gradient, to give the hydroxamic acid product (85 mg, 52%). MS    (M+H)⁺=521.

Example 109trans-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-pyrrolidinecarboxamidebis(trifluoroacetate)

-   (109a) The product from example 108 (50 mg, 0.079 mmol) was mixed    with TFA (1 mL) and CH₂Cl₂ (2 mL) and stirred for 1 h. Concentration    in vacuo provided the title compound (52 mg, 100%). MS (M+H)⁺=421.

Example 110cis-1-[[(1,1-dimethylethyl)oxy]carbonyl]-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-pyrrolidinecarboxamidetrifluoroacetate

-   (110a-b) Following the procedures similar to that used for steps    (101a-b), the intermediate from (108f) was converted to the title    compound. The product was purified by reverse phase HPLC on a Vydac    C-18 semiprep column eluting an acetonitrile:water:TFA gradient, to    give the hydroxamic acid product. MS (M+H)⁺=521.

Example 111cis-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-pyrrolidinecarboxamidebis(trifluoroacetate)

-   (111a) Following the procedure similar to that used for step (109a),    the product from (110a) was converted to the title compound. MS    (M+H)⁺=421.

Example 112(3S,4R)-1-[[(1,1-dimethylethyl)oxy]carbonyl]-N-hydroxy-4-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-3-piperidinecarboxamidetrifluoroacetate

-   (112a) DIEA (82 mL, 2.5 eq) and (BOC)₂O (36.0 g, 1.3 eq) were added    to a solution of methyl 4-oxo-3-piperidinecarboxylate (24.6 g, 137    mmol) in CH₂Cl₂ (600 mL) at 0° C. After at rt overnight, sat NaHCO₃    (50 mL) was added. The mixture was washed with water (2×30 mL),    brine (30 mL), dried (MgSO4) and concentrated in vacuo. Silica gel    chromatography (ethyl acetate-hexane, 50:50) provided the desired    product (29.8 g, 93%).-   (112b) Yb(OTf)₃ (1.41 g, 0.02 eq) was added to a mixture of the    intermediate from (112a) (29.2 g, 113 mmol) and    (R)-α-methylbenzylamine (16.1 mL, 1.1 eq) in benzene. The mixture    was heated to reflux for 3 h with azotropic removal of water using a    Dean-Stark trap. The mixture was concentrated in vacuo. The residue    was filtered through a silica gel pad and the filter cake washed    with ethyl acetate-hexane (10:90) until free of product. The    filtrated was concentrated to give the desired enamine product (40.8    g, 100%). MS (M+H)⁺=361.-   (112c) NaHB(OAc)3 (58.8 g, 2.5 eq) was added to a solution of the    enamine from (112b) (40.0 g, 111 mmol) in acetic acid (180 mL) and    acetonitrile (180 mL) at 0° C. After 2 h at 0° C., the mixture was    concentrated in vacuo. The residue was diluted with CH₂Cl₂ (1 L),    washed with Na₂CO₃ (3×50 mL), brine (50 mL), dried (MgSO₄) and    concentrated in vacuo. Silica gel chromatography (ethyl    acetate-hexane, 10:90 then 20:80) provided the desired amine product    as a 5:1 mixture of two diastereomers as judged by ¹H NMR (37.0 g,    92%). MS (M+H)⁺=363.-   (112d) Pd(OH)₂ on C (6.0 g) was added to the amine from (112c) (36.8    g, 101 mmol) in methanol (600 mL), water (60 mL) and acetic acid (15    mL). The mixture was purged with hydrogen and stirred under balloon    pressure hydrogen overnight. Following removal of catalyst by    filtration, the filtrate was concentrated to give the desired amine    (22.8 g, 87%). MS (M+H)⁺=259.-   (112e) Following the procedure similar to that used for steps    (100a), the amine from (112d) (10.0 g, 38.7 mmol) was coupled with    4-(2-methyl-4-quinolinylmethoxy)benzoic acid. Silica gel    chromatography (ethyl acetate-hexane, 50:50 then 70:30) gave the    desired amide (10.4 g, 50%). The enantiomeric purity of the amide    was improved to >99% ee by crystallization with CHCl₃ (80 mL), ethyl    acetate (10 mL) and hexane (10 mL). The material recovery from the    crystalization was 63%. MS (M+H)⁺=534.-   (112f) Following the procedure similar to that used for steps    (100b), the intermediate from (112e) (80 mg, 0.150 mmol) was    converted to the hydroxamic acid. The product was purified by    reverse phase HPLC on a Vydac C-18 semiprep column eluting an    acetonitrile:water:TFA gradient, to give the desired hydroxamic acid    product (43 mg, 44%). MS (M+H)⁺=535.

Example 113(3S,4S)-1-[[(1,1-dimethylethyl)oxy]carbonyl]-N-hydroxy-4-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-3-piperidinecarboxamidetrifluoroacetate

-   (113a-d) Following the procedures similar to that used for steps    (112b-e), but using (S)-α-methylbenzylamine in step (112b), the    (3R,4S) amide enantiomer was prepared. MS (M+H)⁺=534.-   (113e-f) Following the procedures similar to that used for steps    (101a-b), the amide from (113d) was converted to the title compound.    The product was purified by reverse phase HPLC on a Vydac C-18    semiprep column eluting an acetonitrile:water:TFA gradient, to give    the desired hydroxamic acid product. MS (M+H)⁺=535.

Example 114(3S,4S)-N-hydroxy-4-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-3-piperidinecarboxamidebis(trifluoroacetate)

-   (114a) Following the procedure similar to that used for step (109a),    the product from (113f) was converted to the title compound. MS    (M+H)⁺=435.

Example 115(3S,4R)-N-hydroxy-4-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-3-piperidinecarboxamidebis(trifluoroacetate)

-   (115a) Following the procedure similar to that used for step (109a),    the product from (112f) was converted to the title compound. MS    (M+H)⁺=435.

Example 116(3S,4R)-1-[(butoxy)carbonyl]-N-hydroxy-4-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-3-piperidinecarboxamidetrifluoroacetate

-   (116a) Following the procedure similar to that used for step (109a),    the intermediate from (112e) (2.24 g, 4.20 mmol) was converted to    the desired amine bis-TFA salt (3.16 g, 100%). MS (M+H)⁺=434.-   (116b) DIEA (0.17 mL, 5 eq) and n-butyl chloroformate (30 mg, 1.1    eq) were added to the amine from (116a) (150 mg, 0.199 mmol) in    CH₂Cl₂. After 30 min at rt, ethyl acetate (100 mL) and sat NaHCO₃ (3    mL) were added. The mixture was washed with water (2×3 mL) and brine    (3 mL), dried (MgSO₄) and concentrated in vacuo. The crude material    was taken to the next step without further purification. MS    (M+H)⁺=534.-   (116c) Following the procedures similar to that used for step    (100b), the crude material from (116b) was converted to the title    compound. The product was purified by reverse phase HPLC on a Vydac    C-18 semiprep column eluting an acetonitrile:water:TFA gradient, to    give the desired hydroxamic acid product (38 mg, 29% for two steps).    MS (M+H)⁺=535.

Example 117(3S,4R)-N-hydroxy-1-[[(1-methylethyl)oxy]carbonyl]-4-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-3-piperidinecarboxamidetrifluoroacetate

-   (117a-b) Following the procedures similar to that used for steps    116b and 100b, but with isopropyl chloroformate in step (116b), the    title compound was prepared. The product was purified by reverse    phase HPLC on a Vydac C-18 semiprep column eluting an    acetonitrile:water:TFA gradient, to give the hydroxamic acid    product. MS (M+H)⁺=521.

Example 118(3S,4R)-N-hydroxy-1-(methylsulfonyl)-4-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-3-piperidinecarboxamidetrifluoroacetate

-   (118a-b) Following the procedures similar to that used for steps    116b and 100b, but with MsCl in step (116b), the title compound was    prepared. The product was purified by reverse phase HPLC on a Vydac    C-18 semiprep column eluting an acetonitrile:water:TFA gradient, to    give the hydroxamic acid product. MS (M+H)⁺=513.

Example 119(3S,4R)-N-hydroxy-4-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-1-(phenylsulfonyl)-3-piperidinecarboxamidetrifluoroacetate

-   (119a-b) Following the procedures similar to that used for steps    116b and 100b, but with benzenesulfonyl chloride in step (116b), the    title compound was prepared. The product was purified by reverse    phase HPLC on a Vydac C-18 semiprep column eluting an    acetonitrile:water:TFA gradient, to give the hydroxamic acid    product. MS (M+H)⁺=575.

Example 120(3S,4R)-1-acetyl-N-hydroxy-4-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-3-piperidinecarboxamidetrifluoroacetate

-   (120a-b) Following the procedures similar to that used for steps    116b and 100b, but with acetic anhydride in step (116b), the title    compound was prepared. The product was purified by reverse phase    HPLC on a Vydac C-18 semiprep column eluting an    acetonitrile:water:TFA gradient, to give the hydroxamic acid    product. MS (M+H)⁺=477.

Example 121(3S,4R)-1-benzoyl-N-hydroxy-4-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-3-piperidinecarboxamidetrifluoroacetate

-   (121a-b) Following the procedures similar to that used for steps    116b and 100b, but with benzoyl chloride in step (116b), the title    compound was prepared. The product was purified by reverse phase    HPLC on a Vydac C-18 semiprep column eluting an    acetonitrile:water:TFA gradient, to give the hydroxamic acid    product. MS (M+H)⁺=539.

Example 122(3S,4R)-1-(2,2-dimethylpripionyl)-N-hydroxy-4-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-3-piperidinecarboxamidetrifluoroacetate

-   (122a-b) Following the procedures similar to that used for steps    116b and 100b, but with trimethylacetyl chloride in step (116b), the    title compound was prepared. The product was purified by reverse    phase HPLC on a Vydac C-18 semiprep column eluting an    acetonitrile:water:TFA gradient, to give the hydroxamic acid    product. MS (M+H)⁺=519.

Example 123(3S,4R)-1-(3,3-dimethylbutanoyl)-N-hydroxy-4-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-3-piperidinecarboxamidetrifluoroacetate

-   (123a-b) Following the procedures similar to that used for steps    116b and 100b, but with 3,3-dimethylbutyryl chloride in step (116b),    the title compound was prepared. The product was purified by reverse    phase HPLC on a Vydac C-18 semiprep column eluting an    acetonitrile:water:TFA gradient, to give the hydroxamic acid    product. MS (M+H)⁺=533.

Example 124(3S,4R)-N-hydroxy-4-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-1-(4-morpholinecarbonyl)-3-piperidinecarboxamidetrifluoroacetate

-   (124a-b) Following the procedures similar to that used for steps    116b and 100b, but with 4-morpholinecarbonyl chloride in step    (116b), the title compound was prepared. The product was purified by    reverse phase HPLC on a Vydac C-18 semiprep column eluting an    acetonitrile:water:TFA gradient, to give the hydroxamic acid    product. MS (M+H)⁺=548.

Example 125(3S,4R)-1-(dimethylcarbamyl)-N-hydroxy-4-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-3-piperidinecarboxamidetrifluoroacetate

-   (125a-b) Following the procedures similar to that used for steps    116b and 100b, but with dimethylcarbamyl chloride in step (116b),    the title compound was prepared. The product was purified by reverse    phase HPLC on a Vydac C-18 semiprep column eluting an    acetonitrile:water:TFA gradient, to give the hydroxamic acid    product. MS (M+H)⁺=506.

Example 126(3S,4R)-N-hydroxy-1-methyl-4-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-3-piperidinecarboxamidebis(trifluoroacetate)

-   (126a) DIEA (0.23 mL, 5 eq) and 37% aqueous formaldehyde (24 mg, 1.1    eq) were added to the amine intermediate from (116a) (200 mg, 0.258    mmol) in 1,2-dichloroethane (6 mL). After 30 min at rt, NaHB(OAc)₃    (82 mg, 1.5 eq) was added. After additional 1 h at rt, sat NaHCO₃ (3    mL) and ethyl acetate (100 mL) were added. The mixture was washed    with water (2×5 mL) and brine (5 mL), dried (MgSO₄) and concentrated    in vacuo. The crude material was used in the next step without    further purification. MS (M+H)⁺=448.-   (126b) Following the procedures similar to that used for step    (100b), the crude intermediate from (126a) was converted to the    title compound. The product was purified by reverse phase HPLC on a    Vydac C-18 semiprep column eluting an acetonitrile:water:TFA    gradient, to give the desired hydroxamic acid (50 mg, 32% for two    steps). MS (M+H)⁺=449.

Example 127(3S,4R)-1-ethyl-N-hydroxy-4-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-3-piperidinecarboxamidebis(trifluoroacetate)

-   (127a-b) Following the procedures similar to that used for steps    126a and 100b, but with acetaldehdye in step (126b), the title    compound was prepared. The product was purified by reverse phase    HPLC on a Vydac C-18 semiprep column eluting an    acetonitrile:water:TFA gradient, to give the hydroxamic acid    product. MS (M+H)⁺=463.

Example 128(3S,4R)-N-hydroxy-4-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-1-propyl-3-piperidinecarboxamidebis(trifluoroacetate)

-   (128a-b) Following the procedures similar to that used for steps    126a and 100b, but with propionaldehyde in step (126b), the title    compound was prepared. The product was purified by reverse phase    HPLC on a Vydac C-18 semiprep column eluting an    acetonitrile:water:TFA gradient, to give the hydroxamic acid    product. MS (M+H)⁺=477.

Example 129(3S,4R)-N-hydroxy-1-(1-methylethyl)-4-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-3-piperidinecarboxamidebis(trifluoroacetate)

-   (129a-b) Following the procedures similar to that used for steps    126a and 100b, but with acetone in step (126b), the title compound    was prepared. The product was purified by reverse phase HPLC on a    Vydac C-18 semiprep column eluting an acetonitrile:water:TFA    gradient, to give the hydroxamic acid product. MS (M+H)⁺=477.

Example 130(3S,4R)-1-(cyclopropylmethyl)-N-hydroxy-4-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-3-piperidinecarboxamidebis(trifluoroacetate)

-   (130a-b) Following the procedures similar to that used for steps    126a and 100b, but with cyclopropanecarboxaldehyde in step (126b),    the title compound was prepared. The product was purified by reverse    phase HPLC on a Vydac C-18 semiprep column eluting an    acetonitrile:water:TFA gradient, to give the hydroxamic acid    product. MS (M+H)⁺=489.

Example 131(3S,4R)-1-(2,2-dimethylpropyl)-N-hydroxy-4-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-3-piperidinecarboxamidebis(trifluoroacetate)

-   (131a-b) Following the procedures similar to that used for steps    126a and 100b, but with trimethylacetaldehyde in step (126b), the    title compound was prepared. The product was purified by reverse    phase HPLC on a Vydac C-18 semiprep column eluting an    acetonitrile:water:TFA gradient, to give the hydroxamic acid    product. MS (M+H)⁺=505.

Example 132(3S,4R)-1-benzyl-N-hydroxy-4-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-3-piperidinecarboxamidebis(trifluoroacetate)

-   (132a-b) Following the procedures similar to that used for steps    126a and 100b, but with benzaldehyde in step (126b), the title    compound was prepared. The product was purified by reverse phase    HPLC on a Vydac C-18 semiprep column eluting an    acetonitrile:water:TFA gradient, to give the hydroxamic acid    product. MS (M+H)⁺=525.

Example 133(3S,4R)-1-(2-thiazolylmethyl)-N-hydroxy-4-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-3-piperidinecarboxamidebis(trifluoroacetate)

-   (133a-b) Following the procedures similar to that used for steps    126a and 100b, but with 2-thiazolecarboxaldehyde in step (126b), the    title compound was prepared. The product was purified by reverse    phase HPLC on a Vydac C-18 semiprep column eluting an    acetonitrile:water:TFA gradient, to give the hydroxamic acid    product. MS (M+H)⁺=532.

Example 134(3S,4S)-1-[[(1,1-dimethylethyl)oxy]carbonyl]-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamidetrifluoroacetate

-   (134a). A mixture of ethyl 1-benzyl-3-oxo-4-piperidinecarboxylate    hydrochloride (50 g, 168 mmol), (BOC)₂O (50 g, 1.36 eq), Et₃N (35.2    mL, 1.5 eq), Pd(OH)₂ on C (10 g) and ethanol (400 mL) was    hydrogenated at 50 psi overnight. Following removal of catalyst by    filtration, the filtrate was concentrated, diluted with ethyl    acetate (1 L), washed with 0.5 N HCl (300 mL), sat NaHCO₃ (150 mL),    brine (100 mL), dried (MgSO₄) and concentrated in vacuo. Silica gel    chromatography (ethyl acetate-hexane, 5:95 then 10:90) provided the    desired product (39.0 g, 86%). MS (M+H)⁺=272.-   (134b-e) Following the procedures similar to that used for steps    (112b-e), the intermediate from (134a) was converted to the desired    amide. The material obtained through this route was 40% ee as    determined by analytical chiral HPLC. The enantiomeric purity of the    major enantiomer was improved to >99% ee using preparative chiral    HPLC. The minor enantiomer was also collected. MS (M+H)⁺=548.-   (134f) Following the procedures similar to that used for step    (100b), the major enantiomer from (134e) (100 mg, 0.180 mmol) was    converted to the title compound. The product was purified by reverse    phase HPLC on a Vydac C-18 semiprep column eluting an    acetonitrile:water:TFA gradient, to give the desired hydroxamic acid    product (83.5 mg, 72%). MS (M+H)⁺=535.

Example 135(3R,4S)-1-[[(1,1-dimethylethyl)oxy]carbonyl]-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamidetrifluoroacetate

-   (135a-b) Following the procedures similar to that used for steps    (101a-b), the minor enantiomer from (134e) was converted to the    title compound. The product was purified by reverse phase HPLC on a    Vydac C-18 semiprep column eluting an acetonitrile:water:TFA    gradient, to give the hydroxamic acid product. MS (M+H)⁺=535.

Example 136(3R,4S)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamidebis(trifluoroacetate)

-   (136a) Following the procedure similar to that used for step (109a),    the product from (135b) was converted to the title compound. MS    (M+H)⁺=435.

Example 137(3S,4S)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamidebis(trifluoroacetate)

-   (137a) Following the procedure similar to that used for step (109a),    the product from (134f) was converted to the title compound. MS    (M+H)⁺=435.

Example 138(3S,4S)-N-hydroxy-1-[[(2-methylpropyl)oxy]carbonyl]-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamidetrifluoroacetate

-   (138a) Following the procedure similar to that used for step (109a),    the major enantiomer from (134e) (500 mg, 0.913 mmol) was converted    to the desired amine bis-TFA salt (616 mg, 100%). MS (M+H)⁺=448.-   (138b-c) Following the procedures similar to that used for steps    116b and 100b, but with the amine from (138a) and isobutyl    chloroformate in step (116b), the title compound was prepared. The    product was purified by reverse phase HPLC on a Vydac C-18 semiprep    column eluting an acetonitrile:water:TFA gradient, to give the    hydroxamic acid product. MS (M+H)⁺=535.

Example 139(3S,4S)-N-hydroxy-1-(methoxycarbonyl)-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamidetrifluoroacetate

-   (139a-b) Following the procedures similar to that used for steps    116b and 100b, but with the amine from (138a) and methyl    chloroformate in step (116b), the title compound was prepared. The    product was purified by reverse phase HPLC on a Vydac C-18 semiprep    column eluting an acetonitrile:water:TFA gradient, to give the    hydroxamic acid product. MS (M+H)⁺=493.

Example 140(3S,4S)-N-hydroxy-1-[(1-methylethoxy)carbonyl]-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamidetrifluoroacetate

-   (140a-b) Following the procedures similar to that used for steps    116b and 100b, but with the amine from (138a) and isopropyl    chloroformate in step (116b), the title compound was prepared. The    product was purified by reverse phase HPLC on a Vydac C-18 semiprep    column eluting an acetonitrile:water:TFA gradient, to give the    hydroxamic acid product. MS (M+H)⁺=521.

Example 141(3S,4S)-N-hydroxy-1-(methylsulfonyl)-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamidetrifluoroacetate

-   (141a-b) Following the procedures similar to that used for steps    116b and 100b, but with the amine from (138a) and methanesulfonyl    chloride in step (116b), the title compound was prepared. The    product was purified by reverse phase HPLC on a Vydac C-18 semiprep    column eluting an acetonitrile:water:TFA gradient, to give the    hydroxamic acid product. MS (M+H)⁺=513.

Example 142(3S,4S)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-1-(phenylsulfonyl)-4-piperidinecarboxamidetrifluoroacetate

-   (142a-b) Following the procedures similar to that used for steps    116b and 100b, but with the amine from (138a) and benzenesulfonyl    chloride in step (116b), the title compound was prepared. The    product was purified by reverse phase HPLC on a Vydac C-18 semiprep    column eluting an acetonitrile:water:TFA gradient, to give the    hydroxamic acid product. MS (M+H)⁺=575.

Example 147(3S,4S)-1-(3,3-dimethylbutanoyl)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamidetrifluoroacetate

-   (147a-b) Following the procedures similar to that used for steps    116b and 100b, but with the amine from (138a) and t-butylacetyl    chloride in step (116b), the title compound was prepared. The    product was purified by reverse phase HPLC on a Vydac C-18 semiprep    column eluting an acetonitrile:water:TFA gradient, to give the    hydroxamic acid product. MS (M+H)⁺=533.

Example 148(3S,4S)-1-(2,2-dimethylpropionyl)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamidetrifluoroacetate

-   (148a-b) Following the procedures similar to that used for steps    116b and 100b, but with the amine from (138a) and trimethylacetyl    chloride in step (116b), the title compound was prepared. The    product was purified by reverse phase HPLC on a Vydac C-18 semiprep    column eluting an acetonitrile:water:TFA gradient, to give the    hydroxamic acid product. MS (M+H)⁺=519.

Example 149(3S,4S)-1-benzoyl-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamidetrifluoroacetate

-   (149a-b) Following the procedures similar to that used for steps    116b and 100b, but with the amine from (138a) and benzoyl chloride    in step (116b), the title compound was prepared. The product was    purified by reverse phase HPLC on a Vydac C-18 semiprep column    eluting an acetonitrile:water:TFA gradient, to give the hydroxamic    acid product. MS (M+H)⁺=539.

Example 150(3S,4S)-1-[(pyridin-3-yl)carbonyl]-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamidebis(trifluoroacetate)

-   (150a-b) Following the procedures similar to that used for steps    116b and 100b, but with the amine from (138a) and nicotinoyl    chloride in step (116b), the title compound was prepared. The    product was purified by reverse phase HPLC on a Vydac C-18 semiprep    column eluting an acetonitrile:water:TFA gradient, to give the    hydroxamic acid product. MS (M+H)⁺=540.

Example 151(3S,4S)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-1-(2-thiophenecarbonyl)-4-piperidinecarboxamidetrifluoroacetate

-   (151a-b) Following the procedures similar to that used for steps    116b and 100b, but with the amine from (138a) and    2-thiophenecarbonyl chloride in step (116b), the title compound was    prepared. The product was purified by reverse phase HPLC on a Vydac    C-18 semiprep column eluting an acetonitrile:water:TFA gradient, to    give the hydroxamic acid product. MS (M+H)⁺=545.

Example 152(3S,4S)-1-(dimethylcarbamyl)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamidetrifluoroacetate

-   (152a-b) Following the procedures similar to that used for steps    116b and 100b, but with the amine from (138a) and dimethylcarbamyl    chloride in step (116b), the title compound was prepared. The    product was purified by reverse phase HPLC on a Vydac C-18 semiprep    column eluting an acetonitrile:water:TFA gradient, to give the    hydroxamic acid product. MS (M+H)⁺=506.

Example 153(3S,4S)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-1-(4-morpholinecarbonyl)-4-piperidinecarboxamidetrifluoroacetate

-   (153a-b) Following the procedures similar to that used for steps    116b and 100b, but with the amine from (138a) and    4-morpholinecarbonyl chloride in step (116b), the title compound was    prepared. The product was purified by reverse phase HPLC on a Vydac    C-18 semiprep column eluting an acetonitrile:water:TFA gradient, to    give the hydroxamic acid product. MS (M+H)⁺=548.

Example 154(3S,4S)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-1-[[2-(2-thienyl)ethyl]carbamyl]-4-piperidinecarboxamidetrifluoroacetate

-   (154a-b) Following the procedures similar to that used for steps    116b and 100b, but with the amine from (138a) and    2-(thien-2-yl)ethyl isocyanate in step (116b), the title compound    was prepared. The product was purified by reverse phase HPLC on a    Vydac C-18 semiprep column eluting an acetonitrile:water:TFA    gradient, to give the hydroxamic acid product. MS (M+H)⁺=588.

Example 155(3S,4S)-1-[(1,1-dimethylethyl)carbamyl]-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamidetrifluoroacetate

-   (155a-b) Following the procedures similar to that used for steps    116b and 100b, but with the amine from (138a) and t-butyl isocyanate    in step (116b), the title compound was prepared. The product was    purified by reverse phase HPLC on a Vydac C-18 semiprep column    eluting an acetonitrile:water:TFA gradient, to give the hydroxamic    acid product. MS (M+H)⁺=534.

Example 156(3S,4S)-N-hydroxy-1-methyl-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamidebis(trifluoroacetate)

-   (156a-b) Following the procedures similar to that used for steps    126a and 100b, but with the amine from (138a) and para-formaldehyde    in step (126a), the title compound was prepared. The product was    purified by reverse phase HPLC on a Vydac C-18 semiprep column    eluting an acetonitrile:water:TFA gradient, to give the hydroxamic    acid product. MS (M+H)⁺=449.

Example 157(3S,4S)-1-ethyl-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamidebis(trifluoroacetate)

-   (157a-b) Following the procedures similar to that used for steps    126a and 100b, but with the amine from (138a) and acetaldehyde in    step (126a), the title compound was prepared. The product was    purified by reverse phase HPLC on a Vydac C-18 semiprep column    eluting an acetonitrile:water:TFA gradient, to give the hydroxamic    acid product. MS (M+H)⁺=463.

Example 158(3S,4S)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-1-propyl-4-piperidinecarboxamidebis(trifluoroacetate)

-   (158a-b) Following the procedures similar to that used for steps    126a and 100b, but with the amine from (138a) and propionaldehyde in    step (126a), the title compound was prepared. The product was    purified by reverse phase HPLC on a Vydac C-18 semiprep column    eluting an acetonitrile:water:TFA gradient, to give the hydroxamic    acid product. MS (M+H)⁺=477.

Example 159(3S,4S)-N-hydroxy-1-(1-methylethyl)-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamidebis(trifluoroacetate)

-   (159a-b) Following the procedures similar to that used for steps    126a and 100b, but with the amine from (138a) and acetone in step    (126a), the title compound was prepared. The product was purified by    reverse phase HPLC on a Vydac C-18 semiprep column eluting an    acetonitrile:water:TFA gradient, to give the hydroxamic acid    product. MS (M+H)⁺=477.

Example 160(3S,4S)-1-cyclobutyl-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamidebis(trifluoroacetate)

-   (160a-b) Following the procedures similar to that used for steps    126a and 100b, but with the amine from (138a) and cyclobutanone in    step (126a), the title compound was prepared. The product was    purified by reverse phase HPLC on a Vydac C-18 semiprep column    eluting an acetonitrile:water:TFA gradient, to give the hydroxamic    acid product. MS (M+H)⁺=489.

Example 161(3S,4S)-1-butyl-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamidebis(trifluoroacetate)

-   (161a-b) Following the procedures similar to that used for steps    126a and 100b, but with the amine from (138a) and butyraldehyde in    step (126a), the title compound was prepared. The product was    purified by reverse phase HPLC on a Vydac C-18 semiprep column    eluting an acetonitrile:water:TFA gradient, to give the hydroxamic    acid product. MS (M+H)⁺=491.

Example 162(3S,4S)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-1-(2-methylpropyl)-4-piperidinecarboxamidebis(trifluoroacetate)

-   (162a-b) Following the procedures similar to that used for steps    126a and 100b, but with the amine from (138a) and isobutyraldehyde    in step (126a), the title compound was prepared. The product was    purified by reverse phase HPLC on a Vydac C-18 semiprep column    eluting an acetonitrile:water:TFA gradient, to give the hydroxamic    acid product. MS (M+H)⁺=491.

Example 163(3S,4S)-1-(cyclopropylmethyl)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamidebis(trifluoroacetate)

-   (163a-b) Following the procedures similar to that used for steps    126a and 100b, but with the amine from (138a) and    cyclopropanecarboxaldehyde in step (126a), the title compound was    prepared. The product was purified by reverse phase HPLC on a Vydac    C-18 semiprep column eluting an acetonitrile:water:TFA gradient, to    give the hydroxamic acid product. MS (M+H)⁺=489.

Example 164(3S,4S)-1-(2,2-dimethylpropyl)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamidebis(trifluoroacetate)

-   (164a-b) Following the procedures similar to that used for steps    126a and 100b, but with the amine from (138a) and    trimethylacetaldehyde in step (126a), the title compound was    prepared. The product was purified by reverse phase HPLC on a Vydac    C-18 semiprep column eluting an acetonitrile:water:TFA gradient, to    give the hydroxamic acid product. MS (M+H)⁺=505.

Example 165(3S,4S)-1-cyclopentyl-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamidebis(trifluoroacetate)

-   (165a-b) Following the procedures similar to that used for steps    126a and 100b, but with the amine from (138a) and cyclopentanone in    step (126a), the title compound was prepared. The product was    purified by reverse phase HPLC on a Vydac C-18 semiprep column    eluting an acetonitrile:water:TFA gradient, to give the hydroxamic    acid product. MS (M+H)⁺=503.

Example 166(3S,4S)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-1-(4-tetrahydropyranyl)-4-piperidinecarboxamidebis(trifluoroacetate)

-   (166a-b) Following the procedures similar to that used for steps    126a and 100b, but with the amine from (138a) and    tetrahydro-4H-pyran-4-one in step (126a), the title compound was    prepared. The product was purified by reverse phase HPLC on a Vydac    C-18 semiprep column eluting an acetonitrile:water:TFA gradient, to    give the hydroxamic acid product. MS (M+H)⁺=519.

Example 167(3S,4S)-1-benzyl-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamidebis(trifluoroacetate)

-   (167a-b) Following the procedures similar to that used for steps    126a and 100b, but with the amine from (138a) and benzaldehyde in    step (126a), the title compound was prepared. The product was    purified by reverse phase HPLC on a Vydac C-18 semiprep column    eluting an acetonitrile:water:TFA gradient, to give the hydroxamic    acid product. MS (M+H)⁺=525.

Example 168(3S,4S)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-1-(2-thiazolylmethyl)-4-piperidinecarboxamidebis(trifluoroacetate)

-   (168a-b) Following the procedures similar to that used for steps    126a and 100b, but with the amine from (138a) and    2-thiazolecarboxaldehyde in step (126a), the title compound was    prepared. The product was purified by reverse phase HPLC on a Vydac    C-18 semiprep column eluting an acetonitrile:water:TFA gradient, to    give the hydroxamic acid product. MS (M+H)⁺=532.

Example 169(3S,4S)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-1-(4-pyridinylmethyl)-4-piperidinecarboxamidebis(trifluoroacetate)

-   (169a-b) Following the procedures similar to that used for steps    126a and 100b, but with the amine from (138a) and    4-pyridinecarboxaldehyde in step (126a), the title compound was    prepared. The product was purified by reverse phase HPLC on a Vydac    C-18 semiprep column eluting an acetonitrile:water:TFA gradient, to    give the hydroxamic acid product. MS (M+H)⁺=526.

Example 170(3S,4S)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-1-(2-pyridinylmethyl)-4-piperidinecarboxamidebis(trifluoroacetate)

-   (170a-b) Following the procedures similar to that used for steps    126a and 100b, but with the amine from (138a) and    2-pyridinecarboxaldehyde in step (126a), the title compound was    prepared. The product was purified by reverse phase HPLC on a Vydac    C-18 semiprep column eluting an acetonitrile:water:TFA gradient, to    give the hydroxamic acid product. MS (M+H)⁺=526.

Example 171(3S,4S)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-1-(3-pyridinylmethyl)-4-piperidinecarboxamidebis(trifluoroacetate)

-   (171a-b) Following the procedures similar to that used for steps    126a and 100b, but with the amine from (138a) and    3-pyridinecarboxaldehyde in step (126a), the title compound was    prepared. The product was purified by reverse phase HPLC on a Vydac    C-18 semiprep column eluting an acetonitrile:water:TFA gradient, to    give the hydroxamic acid product. MS (M+H)⁺=526.

Example 172(3S,4S)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-1-(trans-3-phenyl-2-propenyl)-4-piperidinecarboxamidebis(trifluoroacetate)

-   (172a-b) Following the procedures similar to that used for steps    126a and 100b, but with the amine from (138a) and    trans-cinnamaldehyde in step (126a), the title compound was    prepared. The product was purified by reverse phase HPLC on a Vydac    C-18 semiprep column eluting an acetonitrile:water:TFA gradient, to    give the hydroxamic acid product. MS (M+H)⁺=551.

Example 173(3S,4S)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-1-phenyl-4-piperidinecarboxamidebis(trifluoroacetate)

-   (173a) A mixture of the amine from (138a) (100 mg, 0.223 mmol, free    base), benzeneboronic acid (54.5 mg, 2 eq), copper(II) acetate    monohydrate (133.8 mg, 3 eq), pyridine (0.054 mL, 3 eq), 4 A    molecular sieve (165 mg) and CH₂Cl₂ (2 mL) were stirred overnight    with the flask open to the atmosphere. The mixture was filtered and    the filtrate concentrated in vacuo. Silica gel chromatography (ethyl    acetate-hexane, 60:40 then 70:30) provided the desired product (94    mg, 80%). MS (M+H)⁺=524.-   (173b) Following the procedures similar to that used for step    (100b), the intermediate from (173a) (94 mg, 0.180 mmol) was    converted to the title compound. The product was purified by reverse    phase HPLC-on a Vydac C-18 semiprep column eluting an    acetonitrile:water:TFA gradient, to give the desired hydroxamic acid    (74 mg, 56%). MS (M+H)⁺=511.

Example 174 (3R,4S)-1-(2,2-dimethylpropionyl)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamidetrifluoroacetate

-   (174a-b) Following the procedures similar to that used for steps    101a and 109a, the minor enantiomer from (134e) was epimerized with    DBU and deprotected. The product was purified by reverse phase HPLC    on a Vydac C-18 semiprep column eluting an acetonitrile:water:TFA    gradient, to give the trans isomer. MS (M+H)⁺=448.-   (174c-d) Following the procedures similar to that used for steps    116b and 100b, but with the amine from (174b) and trimethylacetyl    chloride in step (116b), the title compound was prepared. The    product was purified by reverse phase HPLC on a Vydac C-18 semiprep    column eluting an acetonitrile:water:TFA gradient, to give the    desired hydroxamic acid. MS (M+H)⁺=519.

Example 175(3R,4S)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-1-methyl-4-piperidinecarboxamidebis(trifluoroacetate)

-   (175a-b) Following the procedures similar to that used for steps    126a and 100b, but with the amine from (174b) and para-formaldehyde    in step (126a), the title compound was prepared. The product was    purified by reverse phase HPLC on a Vydac C-18 semiprep column    eluting an acetonitrile:water:TFA gradient, to give the hydroxamic    acid product. MS (M+H)⁺=449.

Example 176(3R,4S)-1-(dimethylcarbamyl)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamidetrifluoroacetate

-   (176a-b) Following the procedures similar to that used for steps    116b and 100b, but with the amine from (174b) and dimethylcarbamyl    chloride in step (116b), the title compound was prepared. The    product was purified by reverse phase HPLC on a Vydac C-18 semiprep    column eluting an acetonitrile:water:TFA gradient, to give the    hydroxamic acid product. MS (M+H)⁺=506.

Example 177(3S,4S)-1-hexyl-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamidebis(trifluoroacetate)

-   (177a-b) Following the procedures similar to that used for steps    126a and 100b, but using the amine from (138a) and hexanal in step    (126a), the title compound was prepared. The product was purified by    reverse phase HPLC on a Vydac C-18 semiprep column eluting an    acetonitrile:water:TFA gradient, to give the hydroxamic acid    product. MS (M+H)⁺=519.

Example 178(3S,4S)-1-(2-fluoroethyl)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamidebis(trifluoroacetate)

-   (178a) A mixture of the amine from (138a) (800 mg, 1.20 mmol),    1-bromo-2-fluoroehtane (0.27 mL), 3 eq), K₂CO₃ (1.20 g, 10 eq) and    NaI (580 mg, 3 eq) in acetone (20 mL) was heated to reflux for 6 h,    cooled to rt and filtered. The filtrate was concentrated and    purified by silica gel chromatography (methanol-dichloromethane,    5:95) to give the desired product (450 mg, 76%). MS (M+H)⁺=538.-   (178b) Following the procedures similar to that used for step    (100b), the intermediate from (178a) (350 mg, 0.710 mmol) was    converted to the title compound. The product was purified by reverse    phase HPLC on a Vydac C-18 semiprep column eluting an    acetonitrile:water:TFA gradient, to give the desired hydroxamic acid    (170 mg, 34%). MS (M+H)⁺=481.

Example 179(3S,4S)-1-(2,2-difluoroethyl)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamidebis(trifluoroacetate)

-   (179a-b) Following the procedures similar to that used for steps    (178a and 100b), but the amine from (138a) and    2-bromo-1,1-difluoroethane in step (178a), the title compound was    prepared. The product was purified by reverse phase HPLC on a Vydac    C-18 semiprep column eluting an acetonitrile:water:TFA gradient, to    give the hydroxamic acid product. MS (M+H)⁺=499.

Example 180(3S,4S)-N-hydroxy-1-(1-methylpropyl)-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamidebis(trifluoroacetate)

-   (180a-b) Following the procedures similar to that used for steps    (126a and 100b), but using the amine from (138a) and 2-butanone in    step (126a), the title compound was prepared. The product was    purified by reverse phase HPLC on a Vydac C-18 semiprep column    eluting an acetonitrile:water:TFA gradient, to give the hydroxamic    acid product. MS (M+H)⁺=491.

Example 181(3S,4S)-1-(1-ethylpropyl)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamidebis(trifluoroacetate)

-   (181a-b) Following the procedures similar to that used for steps    (126a and 100b), but using the amine from (138a) and 3-pentanone in    step (126a), the title compound was prepared. The product was    purified by reverse phase HPLC on a Vydac C-18 semiprep column    eluting an acetonitrile:water:TFA gradient, to give the hydroxamic    acid product. MS (M+H)⁺=505.

Example 182(3S,4S)-1-[l-[[(1,1-dimethylethyl)oxy]carbonyl]-4-tetrahydropiperidinyl]-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamidebis(trifluoroacetate)

-   (182a-b) Following the procedures similar to that used for steps    (126a and 100b), but using the amine from (138a) and    Boc-4-piperidone in step (126a), the title compound was prepared.    The product was purified by reverse phase HPLC on a Vydac C-18    semiprep column eluting an acetonitrile:water:TFA gradient, to give    the hydroxamic acid product. MS (M+H)⁺=618.

Example 183(3S,4S)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-1-(4-tetrahydropiperidinyl)-4-piperidinecarboxamidetris(trifluoroacetate)

-   (183a) Following the procedure similar to that used for step (109a),    the product from (182b) was converted to the title compound. MS    (M+H)⁺=518.

Example 184(3S,4S)-1-[1-[[(1,1-dimethylethyl)oxy]carbonyl]-3-tetrahydropyrrolidinyl]-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamidebis(trifluoroacetate)

-   (184a-b) Following the procedures similar to that used for steps    (126a and 100b), but using the amine from (138a) and    N-Boc-3-pyrrolidinone in step (126a), the title compound was    prepared. The product was purified by reverse phase HPLC on a Vydac    C-18 semiprep column eluting an acetonitrile:water:TFA gradient, to    give the hydroxamic acid product. MS (M+H)⁺=604.

Example 185(3S,4S)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-1-(3-tetrahydropyrrolidinyl)-4-piperidinecarboxamidetris(trifluoroacetate)

-   (185a) Following the procedure similar to that used for step (109a),    the product from (184b) was converted to the title compound. MS    (M+H)⁺=505.

Example 186(3S,4S)-1-(1,1-dimethyl-2-propynyl)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamidebis(trifluoroacetate)

-   (186a) A solution of 3-chloro-3-methyl-1-butyne (0.51 ml, 1 eq) in    dichloromethane (2 mL) was added dropwise to a mixture of the amine    from (138a) (2.00 g, 4.47 mmol), CuCl (1 mg), Cu (1 mg), Et₃N (1.30    mL, 2 eq), water (15 mL) and dichloromethane (30 mL). After stirring    under N₂ for 4 days, the mixture was diluted with dichloromethane    and water. The organic phase was separated and purified by silica    gel chromatography (methanol-dichloromethane, 5:95) to give the    desired product (1.76 g, 76%). MS (M+H)⁺=514.-   (186b) Following the procedures similar to that used for step    (100b), the intermediate from (186a) (200 mg, 0.389 mmol) was    converted to the title compound. The product was purified by reverse    phase HPLC on a Vydac C-18 semiprep column eluting an    acetonitrile:water:TFA gradient, to give the desired hydroxamic acid    (95 mg, 33%). MS (M+H)⁺=501.

Example 187(3S,4S)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-1-(3-thiophenylmethyl)-4-piperidinecarboxamidebis(trifluoroacetate)

-   (187a-b) Following the procedures similar to that used for steps    (126a and 100b), but using the amine from (138a) and    3-thiophenecarboxaldehyde in step (126a), the title compound was    prepared. The product was purified by reverse phase HPLC on a Vydac    C-18 semiprep column eluting an acetonitrile:water:TFA gradient, to    give the hydroxamic acid product. MS (M+H)⁺=531.

Example 188(3S,4S)-N-hydroxy-1-(1-methylethyl)-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-1-oxo-4-piperidinecarboxamidetrifluoroacetate

-   (188a) Following the procedures similar to that used for steps    (126a), but using the amine from (138a) (4.00 g, 5.92 mmol) and    acetone, the title compound was prepared. Silica gel chromatography    (methanol-dichloromethane, 5:95 then 7:93) gave the desired product    (2.36 g, 81%). MS (M+H)⁺=490.-   (188b) m-CPBA (102 mg, 1 eq, 55% pure) was added to a solution of    the tert-amine from (188a) (160 mg, 0.327 mmol) in dichloromethane    (4 mL). After 30 min at rt, the mixture was treated with saturated    NaHSO₃ (1.5 mL) and saturated NaHCO₃ (1.5 mL), and immediately    extracted with ethyl acetate. The extracts were washed with brine,    dried and concentrated (MgSO₄). Silica gel chromatography    (methanol-dichloromethane, 5:95 then 10:90) gave the tertiary amine    N-oxide (140 mg, 85%). MS (M+H)⁺=506.-   (188c) Following the procedures similar to that used for step    (100b), the intermediate from (188b) (30 mg, 0.059 mmol) was    converted to the title compound. The product was purified by reverse    phase HPLC on a Vydac C-18 semiprep column eluting an    acetonitrile:water:TFA gradient, to give the desired hydroxamic acid    (25 mg, 69%). MS (M+H)⁺=493.

Example 189(3S,4S)-N-hydroxy-1-(1-methylethyl)-3-[[[4-[(2-methyl-1-oxo-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamidetrifluoroacetate

-   (189a) The momo-N-oxide from (188b) (110 mg, 0.218 mmol) was    dissolved in dichloromethane. (2 mL) and treated with m-CPBA (68.3    mg, 1 eq, 55% pure) for 30 min. TLC showed clean conversion to the    bis-N-oxide product. The mixture was treated with saturated NaHSO₃    (1.5 mL) and saturated NaHCO₃ (1.5 mL), and extracted with ethyl    acetate. The NaHSO₃ treatment resulted in partial reduction of the    tertiary amine N-oxide and therefore gave a mixture of bis-N-oxide    and quinoline mono-N-oxide. The extracts were washed with brine,    dried and concentrated (MgSO₄). Silica gel chromatography    (methanol-dichloromethane, 5:95 then 8:92 then 10:90 then 15:85)    gave the mono-N-oxide at the quinoline nitrogen (50 mg, 44%) and    bis-N-oxide (40 mg, 35%). MS for mono-N-oxide (M+H)⁺=506, for    bis-N-oxide (M+H)⁺=522.-   (189b) Following the procedures similar to that used for step    (100b), the mono-N-oxide from (189a) (48 mg, 0.095 mmol) was    converted to the title compound. The product was purified by reverse    phase HPLC on a Vydac C-18 semiprep column eluting an    acetonitrile:water:TFA gradient, to give the desired hydroxamic acid    (30 mg, 52%). MS (M+H)⁺=493.

Example 190(3S,4S)-N-hydroxy-1-(1-methylethyl)-3-[[[4-[(2-methyl-1-oxo-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-1-oxo-4-piperidinecarboxamide

-   (190a) Following the procedures similar to that used for step    (100b), the bis-N-oxide from (189a) (38 mg, 0.073 mmol) was    converted to the title compound. The product was purified by reverse    phase HPLC on a Vydac C-18 semiprep column eluting an    acetonitrile:water:TFA gradient, to give the desired hydroxamic acid    (23 mg, 62%). MS (M+H)⁺=509.

Example 191(3S,4S)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-1-[2-(4-morpholinyl)-2-oxoethyl]-4-piperidinecarboxamidebis(trifluoroacetate)

-   (191a) A mixture of the amine from (138a) (2.00 g, 2.96 mmol),    t-butyl bromoacetate (1.15 g, 2 eq), Cs2CO3 (4.82 g, 5 eq) and DMSO    (25 mL) was stirred at rt for 1 h. Following addition of sat NH₄Cl    (15 mL) and ethyl acetate (200 mL), the mixture was washed with    water (2×10 mL), brine (10 mL), dried (MgSO₄) and concentrated.    Silica gel chromatography (ethyl acetate) provided the desired    product (1.40 g, 80%). MS (M+H)⁺=562.-   (191b) The t-butyl eater from (191a) (1.20 g, 2.14 mmol) was treated    with TFA (5 mL) in dichloromethane (5 mL) for 3 h and concentrated    to give the desired carboxylic acid (1.70 g, 100%). MS (M+H)⁺=506.-   (191c) Following the procedure similar to that used for steps    (100a), The acid from (191b) (300 mg, 0.378 mmol) was coupled with    morpholine. Silica gel chromatography (methanol-dichloromethane,    5:95) gave the desired amide (130 mg, 59%). MS (M+H)⁺=575.-   (191d) Following the procedures similar to that used for step    (100b), the product from (191c) (130 mg, 0.223 mmol) was converted    to the title compound. The product was purified by reverse phase    HPLC on a Vydac C-18 semiprep column eluting an    acetonitrile:water:TFA gradient, to give the desired hydroxamic acid    (70 mg, 53%). MS (M+H)⁺=562.

Example 192(3S,4S)-1-[2-(N,N-dimethylamino)-2-oxoethyl]-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamidebis(trifluoroacetate)

-   (192a-b) Following the procedures similar to that used for steps    (100a-b), but using the acid from (191b) and dimethylamine in step    (100a), the title compound was prepared. The product was purified by    reverse phase HPLC on a Vydac C-18 semiprep column eluting an    acetonitrile:water:TFA gradient, to give the hydroxamic acid    product. MS (M+H)⁺=520.

Example 193(3S,4S)-1-(t-butylsulfonyl)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamidetrifluoroacetate

-   (193a) A precooled solution (0° C.) of t-Butylsulfinyl chloride (210    mg, 2 eq) in dichloromethane (10 mL) was added dropwise to a    solution of triethylamine (1.03 mL, 10 eq) and the amine from (138a)    (500 mg, 0.74 mmol) in dichloromethane (10 mL) at 0° C. After 1 h at    0° C., the mixture was quenched with sat NaHCO₃ and extracted with    dichloromethane. The extracts were dried (MgSO₄) and concentrated.    Silica gel chromatography (methanol-dichloromethane, 5:95) gave the    desired sulfinamide (400 mg, 98%) as a 1:1 mixture epimeric at    sulfur center. MS (M+H)⁺=552.-   (193b) Ruthenium(III) chloride monohydrate (0.4 mg) and NaIO₄ (46    mg, 1.2 eq) were added to a mixture of the sulfinamide from (193a)    (100 mg, 0.180 mmol), dichloromethane (2 mL), acetonitrile (2 mL)    and water (3 mL) at 0° C. After 1 h at 0° C., the mixture was    extracted with dichloromethane. The combined extracts were dried    (MgSO₄) and concentrated to give the desired sulfonamide as a crude    material. MS (M+H)⁺=568.-   (193c) Following the procedures similar to that used for step    (100b), the crude product from (193b) was converted to the title    compound. The product was purified by reverse phase HPLC on a Vydac    C-18 semiprep column eluting an acetonitrile:water:TFA gradient, to    give the desired hydroxamic acid (47 mg, 39% for two steps). MS    (M+H)⁺=555.

Example 194(3S,4S)-1-(t-butylsulfonyl)-N-hydroxy-3-[[[4-[(2-methyl-1-oxo-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide

-   (194a) Following a procedure similar to that used for step (189a),    the sulfinamide from (193a) (220 mg, 0.400 mmol) was oxidized to the    sulfonamide quinoline N-oxide (250 mg crude weight). MS (M+H)⁺=584.-   (194b) Following the procedures similar to that used for step    (100b), the crude product from (194a) (100 mg) was converted to the    title compound. The product was purified by reverse phase HPLC on a    Vydac C-18 semiprep column eluting an acetonitrile:water:TFA    gradient, to give the desired hydroxamic acid (64 mg, 65% for two    steps). MS (M+H)⁺=571.

Example 195(3S,4S)-1-(benzenesulfonyl)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamidetrifluoroacetate

-   (195a-b) Following the procedures similar to that used for steps    (116b and 100b), but using the amine from (138a) and benzenesulfonyl    chloride in step (116b), the title compound was prepared. The    product was purified by reverse phase HPLC on a Vydac C-18 semiprep    column eluting an acetonitrile:water:TFA gradient, to give the    hydroxamic acid product. MS (M+H)⁺=575.

Example 196(3S,4S)-1-(t-butylsulfinyl)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamidetrifluoroacetate

-   (196a) Following the procedures similar to that used for step    (100b), the 1:1 mixture of sulfinamide from (193a) was converted to    the title compound. The two isomers were separated by reverse phase    HPLC on a Vydac C-18 semiprep column eluting an    acetonitrile:water:TFA gradient, to give the desired hydroxamic    acids. MS (M+H)⁺=539.

Example 197(3S,4S)-N-hydroxy-1-(2-hydroxylethyl)-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamidebis(trifluoroacetate)

-   (197a) Following the procedure similar to that used for step (126a),    the amine from (138a) (225 mg, 0.333 mmol) was reacted with    (t-butyldimethylsilyloxy)acetaldehyde via reductive amination.    Silica gel chromatography (ethyl acetate-hexane, 30:70, then    methanol-dichloromethane, 5:95) gave the desired product (150 mg,    74%) MS (M+H)⁺=606.-   (197b) A 1 M THF solution of TBAF (0.50 mL, 2 eq) was added to the    product from (197a) (150 mg, 0.248 mmol) in THF (6 mL). The mixture    was stirred for 30 min, diluted with sat NH₄Cl (5 mL) and ethyl    acetate (100 mL), washed with water (5 mL), brine (5 mL), dried    (MgSO₄) and concentrated. Silica gel chromatography    (methanol-dichloromethane, 5:95) gave the desired alcohol (100 mg,    82%). MS (M+H)⁺=492.-   (197c) Following the procedures similar to that used for step    (100b), the product from (197b) (100 mg, 0.203 mmol) was converted    to the title compound. Purification by reverse phase HPLC on a Vydac    C-18 semiprep column eluting an acetonitrile:water:TFA gradient,    gave the desired hydroxamic acid (35 mg, 24%). MS (M+H)⁺=479.

Example 198(3S,4S)-1-[2-[[[(1,1-dimethylethyl)oxy]carbonyl]amino]ethyl]-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamidebis(trifluoroacetate)

-   (198a) Following the procedure similar to that used for step (126a),    the amine from (138a) (200 mg, 0.296 mmol) was reacted with t-butyl    N-(2-oxoethyl)carbamate via reductive amination. Silica gel    chromatography (methanol-dichloromethane, 5:95) gave the desired    product (150 mg, 86%). MS (M+H)⁺=591.-   (198b) Following the procedures similar to that used for step    (100b), the product from (198a) (120 mg, 0.203 mmol) was converted    to the title compound. The product was purified by reverse phase    HPLC on a Vydac C-18 semiprep column eluting an    acetonitrile:water:TFA gradient, to give the hydroxamic acid product    (80 mg, 49%). MS (M+H)⁺=578.

Example 199(3S,4S)-1-(2-aminoethyl)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamidetris(trifluoroacetate)

-   (199a) Following the procedure similar to that used for step (109a),    the product from (198b) was converted to the title compound. MS    (M+H)⁺=478.

Example 200(3S,4S)-1-[2-(N,N-dimethylamino)ethyl]-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamidetris(trifluoroacetate)

-   (200a) Following the procedure similar to that used for step (109a),    the product from (198a) (380 mg, 0.643 mmol) was deprotected to give    the desired product (550 mg, 100%). MS (M+H)⁺=491.-   (200b) Following the procedure similar to that used for step (126a),    the amine from (200a) (300 mg, 0.351 mmol) was reacted with    formaldehyde via reductive amination. Silica gel chromatography    (methanol-dichloromethane-ammonium hydroxide, 10:90:0 then 10:88:2)    gave the dimethylamino product (160 mg, 88%). MS (M+H)⁺=519.-   (200c) Following the procedure similar to that used for step (100b),    the product from (200b) (150 mg, 0.289 mmol) was converted to the    title compound. The product was purified by reverse phase HPLC on a    Vydac C-18 semiprep column eluting an acetonitrile:water:TFA    gradient, to give the hydroxamic acid product (140 mg, 57%). MS    (M+H)⁺=506.

Example 201(3S,4S)-1-[(2S)-2-aminopropyl]-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamidetris(trifluoroacetate)

-   (201a-c) Following the procedures similar to that used for steps    (126a, 100b and 109a), but using the amine from (138a) and    N-t-Boc-L-alaninal in step (126a), the title compound was prepared.    The product was purified by reverse phase HPLC on a Vydac C-18    semiprep column eluting an acetonitrile:water:TFA gradient, to give    the hydroxamic acid product. MS (M+H)⁺=492.

Example 202(3S,4S)-1-[(2R)-2-amino-3-hydroxypropyl]-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamidetris(trifluoroacetate)

-   (202a-c) Following the procedures similar to that used for steps    (126a, 100b and 109a), but using the amine from (138a) and    S-(−)-3-tert-butoxycarbonyl-4-formyl-2,2-dimethyl-1,3-oxazolidine in    step (126a), the title compound was prepared. The product was    purified by reverse phase HPLC on a Vydac C-18 semiprep column    eluting an acetonitrile:water:TFA gradient, to give the hydroxamic    acid product. MS (M+H)⁺=508.

Example 203(3S,4S)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-1-[[(2R)-2-pyrrolidinyl]methyl]-4-piperidinecarboxamidetris(trifluoroacetate)

-   (203a-c) Following the procedures similar to that used for steps    (126a, 100b and 109a), but using the amine from (138a) and    N-(tert-butoxycarbonyl)-D-prolinal in step (126a), the title    compound was prepared. The product was purified by reverse phase    HPLC on a Vydac C-18 semiprep column eluting an    acetonitrile:water:TFA gradient, to give the hydroxamic acid    product. MS (M+H)⁺=518.

Example 204(3S,4R)-N-hydroxy-1-(2-hydroxylethyl)-4-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-3-piperidinecarboxamidebis(trifluoroacetate)

-   (204a-c) Following the procedures similar to that used for steps    (126a, 197b and 100b), but using the amine from (116a) and    (t-butyldimethylsilyloxy)acetaldehyde in step (126a), the title    compound was prepared. The product was purified by reverse phase    HPLC on a Vydac C-18 semiprep column eluting an    acetonitrile:water:TFA gradient, to give the hydroxamic acid    product. MS (M+H)⁺=479.

Example 205(3S,4R)-1-(2-aminoethyl)-N-hydroxy-4-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-3-piperidinecarboxamidetris(trifluoroacetate)

-   (205a-c) Following the procedures similar to that used for steps    (126a, 100b and 109a), but using the amine from (116a) and t-butyl    N-(2-oxoethyl)carbamate in step (126a), the title compound was    prepared. The product was purified by reverse phase HPLC on a Vydac    C-18 semiprep column eluting an acetonitrile:water:TFA gradient, to    give the hydroxamic acid product. MS (M+H)⁺=478.

Example 206(3S,4R)-1-cyclobutyl-N-hydroxy-4-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-3-piperidinecarboxamidebis(trifluoroacetate)

-   (206a-b) Following the procedures similar to that used for steps    (126a and 100b), but using the amine from (116a) and cyclobutanone    in step (126a), the title compound was prepared. The product was    purified by reverse phase HPLC on a Vydac C-18 semiprep column    eluting an acetonitrile:water:TFA gradient, to give the hydroxamic    acid product. MS (M+H)⁺=489.

Example 207(3R,4R)-N-hydroxy-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)tetrahydro-2H-pyran-3-carboxamide

-   (207a) LiHMDS (1.0 M in THF, 52.5 mL, 1.05 eq) was added dropwise to    a −78° C. solution of tetrahydro-4H-pyran-4-one (5.0 g, 50 mmol) in    THF (200 mL). The resulting solution was stirred at −20° C. for 1 h,    then cooled back to −78° C. To this mixture was added methyl    cyanoformate (4.75 mL, 1.2 eq) dropwise. Ten min after completion of    the addition, the reaction was quenched with aqueous NH₄Cl and    extracted with ether (200 mL). The organic layer was washed with    brine (100 mL), dried (MgSO₄), and concentrated. Silica gel column    chromatography (ether-hexane, 1:4, 2:3, then 3:2) yielded an oil    containing both ketone and enol forms of the product (5.4 g, ca. 30%    purity). MS found: (M+H)⁺=159.1.-   (207b) The ester from (207a) was dissolved in benzene (200 mL) and    treated with (R)-α-methylbenzylamine (3 mL) and ytterbium(III)    trifluoromethanesulfonate (200 mg). The mixture was heated to reflux    under Dean-Stark conditions for 2 h, concentrated, and purified by    silica gel column chromatography (ethyl acatete-hexane, 1:4) to    yield the desired enamine as a white solid (3.6 g, 27.5% for 2    steps).-   (207c) The enamine from (207b) (3.5 g, 13.4 mmol) in    acetonitrile-acetic acid (1:1, 80 mL) was treated with NaBH(OAc)₃    and stirred for 2 h at 0° C. Following concentration in vacuo, the    residue was dissolved in ether (200 mL), washed with saturated    NaHCO₃ until the aqueous phase was basic, dried (MgSO₄), and    concentrated to yield an oil (3.39 g, 96%). MS Found: (M+H)⁺=264.3.-   (207d) The intermediate from (207c) (1.86 g, 7.06 mmol) in methanol    (100 mL) was treated with 10% palladium hydroxide on carbon (0.6 g,    3.5% mol) and aqueous 1N hydrochloric acid (10 mL, 1.4 eq) and    stirred under a H₂-balloon for 72 h. The catalyst was removed by    filtration. Removal of solvent provided the desired amine as    hydrochloric acid salt (1.42 g, 100%). MS Found: (M+H)⁺=160.3.-   (207e) To a mixture of the amine from (207d) (1.0 g, 5.11 mmol) and    4-[(2-methyl-4-quinolinyl)methoxy]benzoic acid (1.50 g, 1.0 eq) in    N,N-dimethylformamide (20 ml) was added BOP reagent (2.30 g, 1.02    eq) and N,N-diisopropylethylamine (2.2 mL, 2.5 eq) at room    temperature. After 2 h at room temperature, saturated aqueous NaHCO₃    (50 ml) was added and the mixture extracted with ethyl acetate (2×50    mL), washed with brine (20 mL), dried (MgSO₄) and concentrated.    Silica gel column chromatography (ethyl acetate-hexane, 3:2 then    4:1) yielded the desired amide (1.6 g, 72%). The above amide was    submitted for a chiral HPLC separation (OJ,    hexane-isopropanol-methanol, 60:20:20, 1.2 mL/min @ 240 nM and    ambient temperature) to provide the (3R,4R) isomer in    enantiomerically pure form (980 mg, 58% recovery, >99% ee). MS    Found: (M+H)⁺=435.1.-   (207f) Freshly prepared 1.76 M hydroxylamine solution (example ld)    (20 mL, 20 eq.) was added to the methyl ester (0.78 g, 1.80 mmol)    from reaction (207e) and stirred at room temperature for 10 min. The    mixture was adjusted to pH 7 with 1 N hydrochloric acid. The    resulting precipitate was collected by filtration and recrystallized    from hot methanol (80 mL) to yield the free base form of the    hydroxamic acid. The free base was treated with dichloromethane (30    mL) and trifluoroacetic acid (0.1 mL, 1.5 eq) and stirred until    homogeneous. The mixture was concentrated and lyophilized to afford    the TFA salt of the desired hydroxamic acid (0.50 g, 50%). MS Found:    (M+H)⁺=436.1.

Example 208(3S,4S)-1-tert-butyl-N-hydroxy-3-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-4-piperidinecarboxamidebis(trifluoroacetate)

-   (208a) To a solution of the alcohol (0.95 g, 3.09 mmol) from    reaction (222a) in dichloromethane (30 mL) was added, at 0° C.,    triethylamine (0.65 mL, 1.5 eq), and methanesulfonyl chloride (0.29    mL, 1.2 eq). After 15 min at 0° C., the reaction was quenched with    saturated NaHCO₃ (10 mL), extracted with dichloromethane, washed    with brine, dried (MgSO₄), concentrated and purified by silica gel    chromatography (40% then 50% ethyl acetate/hexane) to yield the    mesylate (0.99 g, 83%). MS found: (M+Na)⁺=408.-   (208b) To a −78° C. solution of the mesylate (0.90 g, 2.33 mmol)    from reaction (208a) in dichloromethane (100 mL) was bubbled ozone    until the reaction solution turned blue. The reaction was purged    with nitrogen until colorless. Triphenylphosphine (0.73 g, 1.2 eq)    was added, and the mixture was stirred at ambient temperature for 2    h, concentrated and purified by silica gel chromatography (60% ethyl    acetate/hexane) to yield the desired aldehyde (0.81 g, 90%). MS    found: (M+Na)⁺=410.-   (208c) A mixture of the aldehyde (0.81 mg, 2.09 mmol) from the    reaction (208b), tert-butylamine (1.14 mL, 5.2 eq) and sodium    triacetoxyborohydride (1.33 g, 3.0 eq) in dichloroethane (40 mL) was    stirred in a sealed flask at room temperature for 4 h, then 80° C.    overnight. The reaction was quenched with saturated NaHCO₃,    extracted with dichloromethane (2×50 mL), washed with brine (50 mL),    dried (MgSO₄), concentrated and purified twice by silica gel    chromatography (60% ethyl acetate/hexane) to yield the desired    cyclized tertiary amine (0.37 g, 40%). MS found: (M+H)⁺=349.-   (208d) A mixture of the amine (0.32 g, 0.92 mmol) from reaction    (208c), Pd/C (64 mg, 20% wt) and 1 N hydrogen chloride in ethyl    ether (1.0 mL) in methanol (20 mL) was stirred under a    hydrogen-balloon for 1 h. After removal of catalyst by filtration,    the filtrate was concentrated to afford the deprotected amine    hydrochloride (0.23 g, 100%). MS found: (M+H)⁺=215.-   (208e) Following a procedure analogous to that used in reaction    (16f), the amine hydrochloride (0.23 g, 0.92 mmol) from reaction    (208d) was coupled with 4-(2-methyl-4-quinolinylmethoxy)benzoic    acid. Silica gel chromatography (3% methanol/dichloromethane)    provided the desired amide (0.37 g, 82%). MS found: (M+H)⁺=490.-   (208f) Following a procedure analogous to that used in reaction    (1d), the methyl ester (0.25 g, 0.51 mmol) from reaction (208e) was    treated with hydroxylamine solution. Purification by reverse phase    HPLC (15-40% acetonitrile/water) yielded the desired hydroxamic acid    (0.26 g, 71%). MS found: (M+H)⁺=491.

Example 209 tert-butyl2-[(3S,4S)-4-[(hydroxyamino)carbonyl]-3-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)piperidinyl]-2-methylpropanoatebis(trifluoroacetate)

-   (209a) The amine from reaction (138a) (250 mg, 0.370 mmol),    tert-butyl 2-bromoisobutyrate (0.69 mL, 10 eq) and potassium    carbonate (760 mg, 15 eq) were added to acetone (20 mL) and heated    to reflux for 24 h. The mixture was cooled to rt and concentrated in    vacuo. Purification of the residue by silica gel column    chromatography (5:95, methanol:methylene chloride) gave the desired    tertiary amine (50 mg, 23%). MS found: (M+H)⁺=590.-   (209b) Following a procedure similar to that used for reaction    (100b), the tertiary amine from reaction (209a) (50 mg, 0.0848 mmol)    was treated with hydroxylamine. Purification by reverse phase HPLC,    using acetonitrile:water:TFA as eluant, provided the title    hydroxamic acid (22 mg, 32%) as bis-TFA salt. MS found: (M+H)⁺=577.

Example 2102-[(3S,4S)-4-[(hydroxyamino)carbonyl]-3-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)piperidinyl]-2-methylpropanoicacid bis(trifluoroacetate)

-   (210a) Following a procedure similar to that used for reaction    (109a), the hydroxamic acid from reaction (209b) was treated with    TFA. Purification by reverse phase HPLC, using    acetonitrile:water:TFA as eluant, provided the title hydroxamic acid    (8 mg, 58%) as bis-TFA salt. MS found: (M+H)⁺=521.

Example 211 methyl2-[(3S,4S)-4-[(hydroxyamino)carbonyl]-3-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)piperidinyl]-2-methylpropanoatebis(trifluoroacetate)

-   (211a) Following a procedure similar to that used for reaction    (209a), The amine from reaction (138a) (200 mg, 0.296 mmol) was    treated with methyl 2-bromoisobutyrate (0.55 mL, 10 eq).    Purification of the residue by silica gel column chromatography    (5:95, methanol:methylene chloride) gave the desired tertiary amine    (150 mg, 93%). MS found: (M+H)⁺=548.-   (211b) Following a procedure similar to that used for reaction    (100b), the tertiary amine from reaction (211a) (150 mg, 0.274 mmol)    was treated with hydroxylamine. Purification by reverse phase HPLC,    using acetonitrile:water:TFA as eluant, provided the title    hydroxamic acid (40 mg, 20%) as bis-TFA salt. MS found: (M+H)⁺=535.

Example 212(3S,4S)-N-hydroxy-3-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-1-[2-(4-morpholinyl)-2-oxoethyl]-4-piperidinecarboxamidebis(trifluoroacetate)

-   (212a) Following a procedure similar to that used for reaction    (209a), The amine from reaction (138a) (2.00 g, 2.96 mmol) was    treated with tert-butyl bromoacetate (1.15 g, 2 eq). Purification of    the residue by silica gel column chromatography (ethyl acetate) gave    the desired tertiary amine (1.40 g, 80%). MS found: (M+H)⁺=562.-   (212b) Following a procedure similar to that used for reaction    (109a), the tertiary amine from reaction (212a) (1.20 g, 2.14 mmol)    was treated with TFA. The mixture was concentrated in vacuo to    provide the desired carboxylic acid (1.70 g, 100%) as bis-TFA salt.    MS found: (M+H)⁺=506.-   (212c) Following a procedure similar to that used for reaction    (16f), the carboxylic acid from reaction (212b) (300 mg, 0.378 mmol)    was treated with morpholine. Purification of the residue by silica    gel column chromatography (5:95, methanol:methylene chloride) gave    the desired amide (130 mg, 60%). MS found: (M+H)⁺=575.-   (212d) Following a procedure similar to that used for reaction    (100b), the amide from reaction (212c) (130 mg, 0.226 mmol) was    treated with hydroxylamine. Purification by reverse phase HPLC,    using acetonitrile:water:TFA as eluant, provided the title    hydroxamic acid (70 mg, 40%) as bis-TFA salt. MS found: (M+H)⁺=562.

Example 213(3S,4S)-1-[2-(dimethylamino)-2-oxoethyl]-N-hydroxy-3-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-4-piperidinecarboxamidebis(trifluoroacetate)

-   (213a) Following a procedure similar to that used for reaction    (16f), the carboxylic acid from reaction (212b) (300 mg, 0.378 mmol)    was treated with dimethylamine hydrogen chloride. The crude amide    (200 mg) was used for the next step without further purification. MS    found: (M+H)⁺=533.-   (213b) Following a procedure similar to that used for reaction    (100b), the amide from reaction (213a) (200 mg, 0.378 mmol) was    treated with hydroxylamine. Purification by reverse phase HPLC,    using acetonitrile:water:TFA as eluant, provided the title    hydroxamic acid (90 mg, 32% for two steps) as bis-TFA salt. MS    found: (M+H)⁺=520.

Example 214(3S,4S)-1-(1,1-dimethyl-2-propenyl)-N-hydroxy-3-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-4-piperidinecarboxamidebis(trifluoroacetate)

-   (214a) A mixture of the intermediate from (186a) (1.0 g, 1.95 mmol)    and Pd/BaSO₄ (0.10 g, 5% wt.) in ethanol (50 mL) was stirred under a    hydrogen balloon for 40 min. After removal of catalyst by    filtration, the filtrate was concentrated and purified by silica gel    chromatography (5% methanol/dichloromethane) to yield the alkene    (0.87 g, 87%). MS found: (M+H)⁺=516.-   (214b) Following a procedure analogous to that used in reaction    (1d), the ethyl ester (0.15 g, 0.29 mmol) from reaction (214a) was    treated with hydroxylamine solution. Purification by reverse phase    HPLC (15-40% acetonitrile/water) yielded the desired hydroxamic acid    (0.09 g, 43%). MS found: (M+H)⁺=503.

Example 215(3S,4S)-N-hydroxy-3-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-1-tert-pentyl-4-piperidinecarboxamidebis(trifluoroacetate)

-   (215a) A mixture of the intermediate from (214a) (0.20 g, 0.388    mmol) and Rh/C (20 mg, 5% wt.) in ethanol (20 mL) was stirred under    a hydrogen balloon for 4 h. After removal of catalyst by filtration,    the filtrate was purified by silica gel chromatography (5%    methanol/dichloromethane) to yield the alkane (0.176 g, 88%). MS    found: (M+H)⁺=518.-   (215b) Following a procedure analogous to that used in reaction    (1d), the ethyl ester (0.12 g, 0.23 mmol) from reaction (215a) was    treated with hydroxylamine solution. Purification by reverse phase    HPLC (15-40% acetonitrile/water) yielded the desired hydroxamic acid    (82 mg, 48%). MS found: (M+H)⁺=505.

Example 216(3S,4S)-N-hydroxy-3-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-1-(2-propynyl)-4-piperidinecarboxamidebis(trifluoroacetate)

-   (216a) A mixture of the free base of the intermediate from (138a)    (0,30 g, 0.67 mmol), propargyl bromide (80% wt. in toluene, 0.1 mL,    0.90 mmol), potassium carbonate (0.46 g, 5 eq) and sodium iodide    (0.135 g, 1.35 eq) in acetone (10 mL) was refluxed for 2 h. The    mixture was then cooled to room temperature, quenched with saturated    NH₄Cl (20 mL), extracted with ethyl acetate (2×20 mL), washed with    brine (10 mL), dried (MgSO₄) and concentrated. Silica gel    chromatography (5% methanol/dichloromethane) yielded the desired    product (0.27 g, 83%). MS found: (M+H)⁺=486.-   (216b) Following a procedure analogous to that used in reaction    (1d), the ethyl ester (0.25 g, 0.52 mmol) from reaction (216a) was    treated with hydroxylamine solution. Purification by reverse phase    HPLC (15-40% acetonitrile/water) yielded the desired hydroxamic acid    (0.26 g, 72%). MS found: (M+H)⁺=473.

Example 217(3S,4S)-1-allyl-N-hydroxy-3-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-4-piperidinecarboxamidebis(trifluoroacetate)

-   (217a-b) Following procedures analogous to that used in reaction    (186a) and (1d), the intermediate from reaction (138a) (0.20 g, 0.45    mmol) was alkylated with allyl bromide, then treated with    hydroxylamine solution. Purification by reverse phase HPLC (15-40%    acetonitrile/water) yielded the desired hydroxamic acid (75 mg, 26%    for 2 steps). MS found: (M+H)⁺=475.

Example 218(3S,4S)-N-hydroxy-1-(1-methyl-2-propynyl)-3-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-4-piperidinecarboxamidebis(trifluoroacetate)

-   (218a-b) Following procedures analogous to that used in reaction    (186a) and (1d), the intermediate from reaction (138a) (0.20 g, 0.45    mmol) was alkylated with 3-chloro-1-butyne, then treated with    hydroxylamine solution. Purification by reverse phase HPLC (15-40%    acetonitrile/water) yielded the desired hydroxamic acid (100.5 mg,    40% for 2 steps). MS found: (M+H)⁺=487.

Example 219(3S,4S)-N-hydroxy-1-(1-methyl-2-propenyl)-3-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-4-piperidinecarboxamidebis(trifluoroacetate)

-   (219a) A mixture of hydroxamic acid from example 218 (20 mg, 0.028    mmol) and 5% wt. Pd/BaSO₄ (4 mg, 20% wt.) in methanol (2 mL) was    stirred under a hydrogen-balloon for 20 min. After removal of    catalyst by filtration, the filtrate was concentrated and    lyophilized to yield the title product (17 mg, 87%). MS found:    (M+H)⁺=489.

Example 220N-{(1R,2S)-4,5-dihydroxy-2-[(hydroxyamino)carbonyl]cyclohexyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamidetrifluoroacetate

-   (220a) To a −20° C. solution of    1-methyl-(1S,2R)-(+)-cis-1,2,3,6-tetrahydrophthalate (2.21 g, 12.0    mmol) and triethylamine (3.34 mL, 2.0 eq) in tetrahydrofuran (30 mL)    was added ethyl chloroformate (1.72 mL, 1.5 eq). After 5 min at −20°    C., the CCl₄/dry ice bath was replaced with ice-water bath. A    solution of sodium azide (1.95 g, 2.5 mmol) in water (10 mL) was    added. The mixture was stirred at ambient temperature for 30 min,    diluted with water (50 mL), extracted with ethyl acetate (2×100 mL),    washed with brine (50 mL), dried (MgSO₄), and concentrated. The oil    residue was treated with benzene (30 mL) and heated to reflux for    1 h. The mixture was finally treated with 1 N hydrochloric acid (24    mL) and stirred at room temperature for 40 h. The aqueous layer was    separated, washed with ethyl ether (2×5 mL), concentrated and pumped    in vacuo to yield the desired amine hydrochloride (1.40 g, 61%).-   (220b) Following a procedure analogous to that used in reaction    (16f), the amine hydrochloride (1.20 g, 5.72 mmol) from reaction    (220a) was coupled with 4-(2-methyl-4-quinolinylmethoxy)benzoic    acid. Silica gel chromatography (60% then 70% ethyl acetate/hexane)    provided the desired amide (1.40 g, 57%). MS found: (M+H)⁺=431.-   (220c) To a mixture of the amide from reaction (220b) (0.30 g, 0.70    mmol) in water (1 mL) and acetone (8 mL) was added    4-methylmorpholine N-oxide (0.16 g, 2 eq) and OsO₄ (4% in water, 0.2    mL, 0.05 eq). After 4 h at room temperature, the reaction was    quenched with 30% NaHSO₃ (3 mL), and stirred for 30 min before    extracted with ethyl acetate (2×50 mL). The extracts were combined,    washed with water (10 mL), brine (10 mL), dried (MgSO₄), and    concentrated. Purification by silica gel chromatography (5%    methanol/dichloromethane) and recrystallization from methanol    yielded the lower Rf isomer as the desired diol (0.16 g, 50%). MS    found: (M+H)⁺=465.-   (220d) Following a procedure analogous to that used in reaction    (1d), the diol from reaction (220c) (0.15 g, 0.30 mmol) was treated    with hydroxylamine solution. Purification by reverse phase HPLC    (15-40% acetonitrile/water) yielded the desired hydroxamic acid (98    mg, 55%). MS found: (M+H)⁺=466.

Example 221(5S)-N-hydroxy-5-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-2-oxo-4-piperidinecarboxamidetrifluoroacetate

-   (221a) A solution of benzyl (S)-(−)-tetrahydro-5-oxo-3-furanyl    carbamate (2.00 g, 8.50 mmol) in THF (50 mL) was added dropwise to    LDA (17.9 mmol, 2.1 eq) in THF (150 mL) at −78° C. over 10 minutes.    After additional 10 min at that temperature, tert-butyl bromoacetate    (3.77 mL, 3 eq) was added. The mixture was stirred at −78° C. for 1    h, quenched with a solution of acetic acid (1 mL) in THF (4 mL) and    warmed to rt. Following removal of solvent in vacuo, the residue was    diluted with ethyl acetate (300 mL), washed with water (2×10 mL),    and brine (10 mL), dried (MgSO₄) and concentrated. 1H NMR analysis    of the crude material indicated presence of two isomers in 3:2    ratio. Silica gel column chromatography (2:8, ethyl acetate:hexanes)    gave the major lactone (950 mg, 32%). MS found: (M+Na)⁺=506.-   (221b) The lactone from reaction (221a) (2.70 g, 7.72 mmol) in THF    (40 mL) was treated with 1 N LiOH (10 mL, 1.3 eq) at 0° C. and    stirred at that temperature for 1 h. The mixture was adjusted to    pH4-5 with 1 N HCl and concentrated. The residue was diluted with    ethyl acetate (200 mL), washed with water (10 mL), brine (10 mL),    dried (MgSO₄) and concentrate in vacuo. The crude carboxylic acid    (3.00 g) was taken to the next step without further purification. MS    found: (M+Na)⁺=390.-   (221c) The crude carboxylic acid from reaction (221b) (3.00 g) in    methanol (20 mL) and benzene (80 mL) was treated with 2.0 M hexane    solution of (trimethylsilyl)diazomethane (5 mL, 1.3 eq) at rt. After    10 min at rt, the mixture was concentrated and purified by silica    gel column chromatography (3:7, ethyl acetate:hexanes) to provide    the desired methyl ester (1.46 g, 50% for two steps). MS found:    (M+Na)⁺=404.-   (221d) The ester from reaction (221c) (780 mg, 2.04 mmol) in    methylene chloride (20 mL) was treated with triethylamine (0.43 mL,    1.5 eq) and methanesulfonyl chloride (0.19 mL, 1.3 eq) at 0° C. and    stirred at that temperature for 1 h. The mixture was quenched with    saturated NaHCO₃ (10 mL) and diluted with ethyl acetate (200 mL).    The mixture was washed with water (10 mL), and brine (10 mL), dried    (MgSO₄) and concentrated. The residue was purified by silica gel    column chromatography (3:7, ethyl acetate:hexanes) to provide the    desired mesylate (870 mg, 93%). MS found: (M+H)⁺=460.-   (221e) The mesylate from reaction (221d) (700 mg, 1.52 mmol) and    sodium azide (990 mg, 10 eq) were dissolved in DMF (10 mL) and    heated to 90° C. for 1 h. The mixture was cooled down to rt, treated    with saturated NaHCO₃ (5 mL) and ethyl acetate (200 mL), washed with    water (10 mL), brine (10 mL), dried (MgSO₄) and concentrate in    vacuo. Purification of the residue by silica gel column    chromatography (2:8, ethyl acetate:hexanes) gave the desired azide    (580 mg, 94%). 1H NMR showed a 4:1 mixture due to partial    epimerization at alpha position of the ester. MS found: (M+H)⁺=407.-   (221f) The azide from reaction (221e) (190 mg, 0.467 mmol) in    methanol (4 mL) was treated with tin(II) chloride (177 mg, 2 eq) and    stirred at rt for 2 h. Additional portion of tin(II) chloride (177    mg, 2 eq) was added and the mixture stirred for 2 h. Following    addition of saturated NaHCO₃ (5 mL) and ethyl acetate (100 mL), the    mixture was washed with water (2×5 mL), and brine (5 mL), dried    (MgSO₄), treated with 1 N HCl in ether (1 mL) and concentrated. The    crude amine hydrochloride salt (220 mg) was taken to the next step    without further purification. MS found: (M+H)⁺=381.-   (221g) Following a procedure similar to that used for reaction    (109a), the amine from reaction (221f) (220 mg) was treated with    TFA. The crude carboxylic acid (250 mg) was taken to the next step    without further purification. MS found: (M+H)⁺=325.-   (221h) Following a procedure similar to that used for reaction    (16f), the carboxylic acid from reaction (212g) (280 mg) was treated    with BOP reagent. Purification of the residue by silica gel column    chromatography (7:3 ethyl acetate:hexane, then 5:95    methanol:methylene chloride) gave the desired lactam (29 mg, 20% for    3 steps). MS found: (M+Na)⁺=329.-   (221i) The lactam from reaction (221h) (29 mg, 0.0948 mmol) in    methanol (8 mL) was treated with 20% Pd(OH)₂ on carbon (20 mg) and    stirred under hydrogen balloon for 2 h. The mixture was filtered and    the filtrate was concentrated to provide the desired amine (16 mg,    100%). MS found: (M+CH₃CN)⁺=205.-   (221j) Following a procedure similar to that used for reaction    (16f), the amine from reaction (212i) (15 mg, 0.0871 mmol) was    coupled with 4-(2-methyl-4-quinolinylmethoxy)benzoic acid.    Purification of the residue by silica gel column chromatography (7:3    ethyl acetate:hexanes, then 5:95 methanol:methylene chloride) gave    the amide compound (25 mg, 64%). MS found: (M+H)⁺=448.-   (221k) Following a procedure similar to that used for reaction    (100b), the intermediate from reaction (221j) (25 mg, 0.0559 mmol)    was treated with hydroxylamine. Purification by reverse phase HPLC,    using acetonitrile:water:TFA as eluant, provided the title    hydroxamic acid (6.5 mg, 21%) as bis-TFA salt. MS found: (M+H)⁺=449.

Example 222(3S,4S)-N-hydroxy-3-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-2-oxo-4-piperidinecarboxamidetrifluoroacetate

-   (222a) Isobutylene (100 mL) was condensed into a solution of    L-ASP(OMe)-OH hydrogen chloride (10.0 g, 54.4 mmol) in dioxane (100    mL) and sulfuric acid (10 mL) in a 350-mL pressure bottle. The    resultant mixture was shaken mechanically at rt for 4 h and poured    into a cold mixture of 1 N NaOH (500 mL) and ether (250 mL). The    aqueous phase was extracted with ethyl acetate (3×200 mL). The    combined organic extracts were washed with brine (30 mL), dried    (MgSO₄) and concentrated to provide the desired ester (2.10 g, 19%).    MS found: (M+H)⁺=204.-   (222b) Following a procedure similar to that used for reaction    (126a), the ester from reaction (222a) (2.10 g, 10.3 mmol) was    treated with benzaldehyde (1.26 mL, 1.2 eq). Purification of the    residue by silica gel column chromatography (3:7 ethyl    acetate:hexanes) gave the desired amine (2.00 g, 66%). MS found:    (M+H)⁺=294.-   (222c) A mixture of the amine for reaction (222b) (2.60 g, 8.86    mmol), potassium phosphate (3.76 g, 2 eq), Lead(II) nitrate (2.35 g,    0.8 eq) and 9-phenylfluorenyl-9-bromide (3.13 g, 1.1 eq) in    acetonitrile (100 mL) was shaken at rt for 15 h. Following addition    of methylene chloride (200 mL and the mixture was filtered through a    silica gel pad. The filtrate was concentrated and purified by silica    gel column chromatography (1:9 ethyl acetate:hexanes) to provide the    desired tertiary amine (4.80 g, 100%). MS found: (M+Na)⁺=556.-   (222d) A 0.5 M toluene solution of potassium    bis(trimethylsilyl)amide (32.2 mL, 2 eq) and allyl iodide (1.47 mL,    2 eq) were added sequentially to a solution of the amine from    reaction (222c) (4.30 g, 8.06 mmol) in THF (100 mL) at −20° C. After    2 h at −20° C., the mixture was quenched with pH7 phosphate buffer    (30 mL). The aqueous phase was extracted with ethyl acetate (2×100    mL). The combined organic layers were washed with brine (20 mL),    dried (MgSO₄) and concentrated. ¹H NMR analysis of the crude    material showed a 5:1 mixture of two isomers. Silica gel column    chromatography (5:95 ethyl acetate:hexanes) gave the major isomer    (3.00 g, 78%). MS found: (M+Na)⁺=596.-   (222e) O₃ was bubbled into a solution of the intermediate from    reaction (222d) (500 mg, 0.872 mmol) in methylene chloride (30 mL)    at −78° C. until the solution turned blue (approximately 2 min). The    mixture was bubbled with N₂ until the blue color disappeared, and    then treated with triphenylphosphine (458 mg, 2 eq). After 4 h at    rt, the mixture was concentrated and purified by silica gel column    chromatography (1:9 ethyl acetate:hexanes) to provide the desired    aldehyde (380 mg, 76%). MS found: (M+Na)⁺=598.-   (222f) Sodium triacetoxyborohydride (423 mg, 6 eq) was added to a    solution of the aldehyde from reaction (222e) (190 mg, 0.330 mmol)    and ammonium acetate (255 mg, 10 eq) in acetic acid (2 mL) and    acetonitrile (2 mL) at 0° C. After 30 minutes at 0° C., another    portion of sodium triacetoxyborohydride (282 mg, 4 eq) was added.    After an additional 30 minutes at 0° C., the mixture was diluted    with ethyl acetate (100 mL) and washed with saturated ammonium    chloride (5 mL), brine (5 mL), dried (MgSO₄) and concentrated.    Purification of the residue by silica gel column chromatography (1:1    ethyl acetate:hexanes, then 1:9 methanol:methylene chloride) gave    the desired primary amine (80 mg, 42%). MS found: (M+H)⁺=577.-   (222g) The amine from reaction (222f) (80 mg, 0.139 mmol) was    treated with TFA (2 mL) at rt for 3 h and concentrated. The crude    carboxylic acid (70 mg) was taken to the next step without further    purification. MS found: (M+H)⁺=281.-   (222h) Following a procedure similar to that used for reaction    (16f), the carboxylic acid from reaction (222g) (70 mg) was treated    with BOP reagent. Purification of the residue by silica gel column    chromatography (1:1 ethyl acetate:hexane, then 5:95    methanol:methylene chloride) gave the desired lactam (25 mg, 69% for    2 steps). MS found: (M+H)⁺=263.-   (222i-k) Following the procedure similar to that used for steps from    (221i-k), but using the lactam from reaction (222h) (25 mg, 0.0953    mmol), the title compound was prepared. The product was purified by    reverse phase HPLC, using acetonitrile:water:TFA as eluant, to    provide the desired hydroxamic acid (6.5 mg, 13% for 3 steps) as    bis-TFA salt. MS found: (M+H)⁺=449.

Example 223(3S,4S)-3-{[4-(2-butynyloxy)benzoyl]amino}-N-hydroxy-1-isopropyl-4-piperidinecarboxamidetrifluoroacetate

-   (223a) The intermediate from reaction (134e) (1.0 g, 1.83 mmol) was    treated with Pd(OH)₂/C (0.20 g, 20% wt.) and ethanol (20 mL). The    resulting mixture stirred under hydrogen balloon overnight. After    removal of catalyst by filtration, the filtrate was concentrated and    purified by silica gel chromatography to yield the phenol (0.60 g,    84%). MS found: (M+H)⁺=393.-   (223b) The phenol from reaction (223a) (0.10 g, 0.26 mmol) was    alkylated with 1-bromo-2-butyne (0.03 mL, 1.3 eq) and K₂CO₃ (0.18 g,    5 eq) in acetonitrile (5 mL) at reflux for 3 h. The mixture was    cooled to room temperature and partitioned between water (10 mL) and    ethyl acetate (50 mL). The organic layer was separated, dried    (MgSO₄), concentrated and purified by silica gel chromatography (40%    ethyl acetate/hexane) to yield the desired product (0.11 g, 99%). MS    found: (M+H)⁺=445.-   (223c) The intermediate from reaction (223b) (0.10 g, 0.23 mmol) was    treated with dichloromethane (2 mL) and trifluoroacetic acid (1 mL)    at room temperature for 1 h, then concentrated and pumped in vacuo    overnight to give the amine TFA salt (0.1 g, 100%). MS found:    (M+H)⁺=345.-   (223d-e) Following procedures analogous to that used in reaction    (16h) and (1d), the intermediate from reaction (223c) (72 mg, 0.16    mmol) was converted to the title compound (37 mg, 71%). MS found:    (M+H)⁺=374.

Example 224(3S,4S)-3-{[4-(2-butynyloxy)benzoyl]amino}-N-hydroxy-4-piperidinecarboxamidetrifluoroacetate

-   (224a) Following a procedure analogous to that used in reaction    (1d), the intermediate from reaction (223c) (27 mg, 0.08 mmol) was    converted to the title compound (10 mg, 28%). MS found: (M+H)⁺=332.

Example 225 tert-butyl(3S,4S)-4-[(hydroxyamino)carbonyl]-3-({4-[(2-methyl-3-pyridinyl)methoxy]benzoyl}amino)-1-piperidinecarboxylatetrifluoroacetate

-   (225a) To a 0° C. solution of the phenol from reaction (223a) (0.10    g, 0.255 mmol) and 2-methyl-3-hydroxymethyl-pyridine (38 mg, 1.2 eq)    in THF (2 mL) was added triphenylphosphine (80 mg, 1.2 eq) and    diethyl azodicarboxylate (0.05 mL, 1.2 eq). After stirred at room    temperature overnight, the mixture was quenched with saturated    NH₄Cl, extracted with ethyl acetate (2×20 mL), dried (MgSO₄),    concentrated and purified by silica gel chromatography (80% ethyl    acetate/hexane) to yield the desired product (0.12 g, 100%). MS    found: (M−H)⁻=496.-   (225b) Following a procedure analogous to that used in reaction    (1d), the intermediate from reaction (225a) (0.12 g, 0.25 mmol) was    treated with hydroxylamine solution. Purification by reverse phase    HPLC (25-50% acetonitrile/water) yielded the desired hydroxamic acid    (67 mg, 52%). MS found: (M+H)⁺=485.

Example 226(3S,4S)-N-hydroxy-3-({4-[(2-methyl-3-pyridinyl)methoxy]benzoyl}amino)-4-piperidinecarboxamidebis(trifluoroacetate)

-   (226a) The hydroxamic acid from reaction (225b) (20 mg, 0.033 mmol)    was treated with dichloromethane (2 mL) and trifluoroacetic acid    (0.2 mL) at room temperature for 1 h. After removal of solvent in    vacuo, the residue was purified by reverse phase HPLC (5-30%    acetonitrile/water) to yield the titled compound (10 mg, 49%).    (M+H)⁺=385.

Example 227 tert-butyl(3S,4S)-3-({4-[(2,5-dimethylbenzyl)oxy]benzoyl}amino)-4-[(hydroxyamino)carbonyl]-1-piperidinecarboxylate

-   (227a) To a mixture of the phenol from reaction (223a) (0.10 g,    0.255 mmol) and 2,5-dimethylbenzyl chloride (0.05 mL, 1.3 eq) in    DMSO (1 mL) was added sodium iodide (51 mg, 1.3 eq) and Cs₂CO₃ (0.25    g, 3.0 eq). After 2 h at room temperature, the reaction mixture was    quenched with saturated NH₄Cl, extracted with ethyl acetate (2×20    mL), dried (MgSO₄), concentrated and purified by silica gel    chromatography (50% ethyl acetate/hexane) to yield the desired    product (0.10 g, 77%). MS found: (M+H)⁺=511.-   (227b) Following a procedure analogous to that used in reaction    (1d), the intermediate from reaction (227a) (0.10 g, 0.20 mmol) was    converted to the desired hydroxamic acid (92 mg, 97%). MS found:    (M−H)⁻=496.

Example 228(3S,4S)-3-({4-[(2,5-dimethylbenzyl)oxy]benzoyl}amino)-N-hydroxy-4-piperidinecarboxamidetrifluoroacetate

-   (228a) The hydroxamic acid from reaction (227b) (26 mg, 0.053 mmol)    was treated with dichloromethane (2 mL) and trifluoroacetic acid (1    mL) at room temperature for 1 h. After removal of solvent in vacuo,    the residue was purified by reverse phase HPLC (30-55%    acetonitrile/water) to yield the titled compound (9.5 mg, 35%).    (M+H)⁺=398.

Example 301(cis,cis)-3-Amino-2-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-(N-hydroxy)cyclohexylcarboxamidebis-trifluoroacetate salt

-   (301a) To a solution of 3-hydroxy-2-nitrobenzoic acid (10 g, 54.6    mmol) in EtOH (150 mL) and benzene (150 mL) was added concentrated    sulfuric acid (40 mL). The mixture was heated at reflux for 48 hours    with azeotropic removal of water and concentrated on a rotary    evaporator. The residue was dissolved in EtOAc (200 mL) and the    resulting solution was washed with saturated NaHCO₃ (2×100 mL) and    brine (2×100 mL). The organic layer was dried (MgSO₄) and    concentrated on a rotary evaporator to give the ethyl ester (11 g,    95%) as a solid. MS-ESI (M+H)⁺=212.1.-   (301b) The above compound (11 g, 52.1 mmol) was mixed with 0.5%    aqueous HCl (200 mL) and PtO₂ (2.2 g) in a Parr bottle. The mixture    was hydrogenated on a Parr shaker at 55 psi for 24 hours. The    catalyst was filtered off and the filtrate was concentrated on a    rotary evaporator. The residue was dried in vacuo to give the crude    ethyl 2-amino-3-hydroxycyclohexylcarboxylate (12 g, 100%). MS-ESI    (M+H)⁺=188.1-   (301c) To a solution of 301b (1.8 g, 8 mmol) and    4-[(2-methyl-4-quinolinyl)methoxy]benzoic acid (1.7 g, 6 mmol) in    DMF (10 mL) cooled in an ice bath was added BOP (3.1 g, 7 mmol)    followed by N-methylmorpholine (3 g, 30 mmol). The mixture was    stirred at room temperature overnight. EtOAc (100 mL) was added and    the solution was washed with brine (2×50 mL), NaHCO₃ (2×50 mL) and    brine (2×50 mL), dried (MgSO₄) and concentrated on a rotary    evaporator. The crude product was chromatographed on a silica gel    column (10% MeOH/CH₂Cl₂) to provide 301c (0.8 g, 30%) as a solid.    MS-ESI (M+H)⁺=449.2.-   (301d) Compound 301c (350 mg, 0.78 mmol) was dissolved in chloroform    (10 mL)/TFA (0.5 mL). To it was added Dess-Martin periodinane (365    mg, 0.86 mmol) and the solution was stirred for 2 hours. Insoluble    material was filtered off and the filtrate was concentrated on a    rotary evaporator to provide the crude ketone product as a solid.    MS-ESI (M+H)⁺=461.2.-   (301e) To a solution of 301d (120 mg, 0.21 mmol) in DMF (2 mL) was    added acetic acid (0.2 mL) followed by NH₄OAc (90 mg, 1.2 mmol) and    Na(OAc)₃BH (120 mg, 0.6 mmol). The mixture was stirred at room    temperature for 3 hours and purified using reverse phase HPLC to    provide the amino product (55 mg, 40%) as a powder. MS-ESI    (M+H)⁺=462.3.-   (301f) Compound 301e (40 mg, 0.058 mmol) was dissolved in DMF (1 mL)    and to it was added N-methylmorpholine (40 mg, 0.4 mmol) followed by    di-tert-butyl-dicarbonate (22 mg, 0.1 mmol). The mixture was stirred    at room temperature for 5 hours and purified using reverse phase    HPLC to provide the Boc-protected product (20 mg, 51%) as a powder.    MS-ESI (M+H)⁺=562.3.-   (301g) A mixture of 301f (20 mg, 0.03 mmol) in MeOH (2 mL) and 1 N    KOH (0.5 mL) was heated at 60° C. for 1 hour and the solution was    concentrated on a rotary evaporator. The residue was dissolved in    DMSO/HOAc and purified using reversed phase HPLC to provide the    carboxylic acid (16 mg, 83%) as a powder. MS-ESI (M+H)⁺=534.2.-   (301h) To a solution of 301g (15 mg, 0.023 mmol) in DMF (1 mL) was    added N-methylmorpholine (20 mg, 0.2 mmol) followed by hydroxylamine    hydrochloride (10 mg, 0.14 mmol). After all solid was dissolved, the    solution was cooled in an ice bath and to it was added BOP (22 mg,    0.05 mmol). The mixture was stirred for 30 min at room temperature.    Purification using reversed phase HPLC provided the hydroxamic acid    (10 mg, 67%) as a powder. MS-ESI (M+H)⁺=549.3.-   (301i) Compound 301h (10 mg) was dissolved in a mixed solvent of 40%    TFA in CH₂Cl₂ (1 mL) and after 30 min, the solvent was removed by    evaporation. The residue was dissolved in water/acetonitrile.    Lyophilization provided the desired product as a powder. MS-ESI    (M+H)⁺=449.3.

Example 302(cis,cis)-3-Methylamino-2-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-(N-hydroxy)cyclohexylcarboxamidebis-trifluoroacetate salt

-   (302a) To a solution of 301d (100 mg, 0.17 mmol) in DMF (1 mL) was    added HOAc (48 mg, 0.8 mmol) followed by methylamine (2 M solution    in THF, 0.4 mL, 0.8 mmol) and Na(OAc)₃BH (80 mg, 0.4 mmol). The    mixture was stirred for 3 hours at room temperature. Purification    using reversed phase HPLC provided the methylamino product (70 mg,    58%) as a powder. MS-ESI (M+H)⁺=476.3.-   (302b) Compound 302a (70 mg, 0.1 mmol) was reacted with    di-tert-butyl-dicarbonate using the procedure described in (301f) to    provide the Boc-protected product (55 mg, 80%) as a powder. MS-ESI    (M+H)⁺=576.3.-   (302c) The final product was obtained by saponification of the ethyl    ester 302b followed by coupling of the carboxylic acid with    hydroxylamine hydrochloride and removal of the Boc group using    procedures similar to those described in (301g)-(301i). MS-ESI    (M+H)⁺=463.3.

Example 303(cis,cis)-3-Dimethylmino-2-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-1-(N-hydroxy)cyclohexylcarboxamidebis-trifluoroacetate salt

-   (303a) To a solution of 302a (100 mg, 0.14 mmol) in DMF (1 mL) was    added formaldehyde (37% aqueous solution, 82 mg, 1 mmol) followed by    N-methylmorpholine (100 mg, 1 mmol) and Na(OAc)₃BH (84 mg, 0.4    mmol). The mixture was stirred for 2 hours at room temperature.    Purification using reversed phase HPLC provided the dimethylamino    product (100 mg, 99%) as a powder. MS-ESI (M+H)⁺=490.2.-   (303b) The final compound was obtained by saponification of the    ethyl ester 303a followed by coupling the resulting carboxylic acid    with hydroxylamine hydrochloride using procedures similar to those    described in (301g) and (301h). MS-ESI (M+H)⁺=477.3.

Example 304(cis,trans)-3-Amino-2-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-1-(N-hydroxy)cyclohexylcarboxamidebis-trifluoroacetate salt

-   (304a) To a solution of 301b (3.6 g, 16 mmol) and 4-benzyloxybenzoic    acid (3.7 g, 16 mmol) in DMF (10 mL) cooled in an ice bath was added    BOP (8 g, 18 mmol) followed by N-methylmorpholine (7.4 mL, 64 mmol).    The mixture was stirred at room temperature overnight and diluted    with EtOAc (150 mL). The resulting solution was washed with NaHCO₃    (2×70 mL) and brine (2×70 mL), dried (MgSO₄) and concentrated on a    rotary evaporator. The residue was chromatographed on a silica gel    column (5% MeOH/CH₂Cl₂) to provide the amide product (2.3 g, 36%) as    a solid. MS-ESI (M+H)⁺=398.2.-   (304b) To a solution of 304a (2.3 g, 5.8 mmol) in CHCl₃ (15 mL)    cooled in an ice bath was added N-methylmorpholine (1.1 mL, 10 mmol)    followed by methanesulfonyl chloride (0.7 g, 6 mmol). The mixture    was stirred in the ice bath for 2 hours and at room temperature    overnight. The solvent was removed by concentration and the residue    was dissolved in EtOAc. The resulting solution was washed with    brine, dried (MgSO₄) and concentrated. Chromatography on a silica    gel column (50% EtOAc/hexane) provided the mesylate (1.6 g, 60%) as    a solid. MS-ESI (M+H)⁺=476.2.-   (304c) A mixture of 304b (1.2 g, 2.5 mmol) and sodium azide (0.33 g,    5.1 mmol) in DMF (15 mL) was heated at 100° C. for 5 hours. DMF was    removed by evaporation in vacuo. The residue was dissolved in EtOAc    and the resulting solution was washed with brine, dried (MgSO₄) and    concentrated. Chromatography on a silica gel column (40%    EtOAc/hexane) provided the azido product (0.69 g, 65%) as a solid.    MS-ESI (M+H)⁺=423.1.-   (304d) Compound 304c (0.69 g, 1.6 mmol) was dissolved in MeOH (20    mL) in a Parr bottle and to it was added 4 N HCl in dioxane (0.5 mL)    followed by 10% Pd—C (0.1 g). The mixture was hydrogenated on a Parr    shaker at 50 psi for 4 hours. The catalyst was filtered off and the    filtrate was concentrated on a rotary evaporator to provide the    amino product (0.55 g, 99%) as a solid. MS-ESI (M+H)⁺=307.2.-   (304e) To a solution of 304d (0.55 g, 1.6 mmol) in THF (15 mL) and    water (2 mL) cooled in an ice bath was added 1 N NaOH (1.6 mL)    followed by NaHCO₃ (0.5 g, 6 mmol) and di-tert-butyl-dicarbonate    (0.35 g, 1.6 mmol). The mixture was stirred 4 hours at room    temperature. EtOAc (150 mL) was added and the solution was washed    with brine (2×60 mL), dried (MgSO₄) and concentrated on a rotary    evaporator to give the crude Boc-protected product that was used for    the next reaction without purification. MS-ESI (M+H)⁺=407.2.-   (304f) A mixture of 304e (0.65 g, 1.6 mmol),    4-chloromethyl-2-methylquinoline (0.36 g, 1.6 mmol) and K₂CO₃ (1 g,    7.2 mmol) in acetone (15 mL) was heated at reflux for 4 hours. EtOAc    (150 mL) was added and the resulting solution was washed with brine    (2×60 mL), dried (MgSO₄), and concentrated on a rotary evaporator.    Purification using reversed phase HPLC provided 304f (0.68 g, 67%)    as a powder. MS-ESI (M+H)⁺=562.3.-   (304g) Compound 304f (0.37 g, 0.65 mmol) was dissolved in MeOH (5    mL) and KOH (0.15 g) in water (1 mL) was added. The mixture was    heated at 50° C. for 1 hour and acidified with 0.2 mL HOAc.    Purification on reversed phase HPLC provided the carboxylic acid    (0.25 g, 70%) as a powder. MS-ESI (M+H)⁺=534.2.-   (304h) To a solution of 304g (58 mg, 0.1 mmol) in DMF (2 mL) was    added hydroxylamine hydrochloride (32 mg, 0.4 mmol) followed by    N-methylmorpholine (0.06 mL, 0.5 mmol). After all solid was    dissolved, the solution was cooled in an ice bath. To it was added    BOP (54 mg, 0.12 mmol) and the mixture was stirred for 1 hour.    Purification on reversed phase HPLC provided the hydroxamic acid as    a powder. MS-ESI (M+H)⁺=549.2.-   (304i) Compound 304h (30 mg) was treated with TFA (1 mL)/CH₂Cl₂ (3    mL) for 20 min and the solution was concentrated on a rotary    evaporator. The residue was taken up in water/acetonitrile.    Lyophilization provided the final product as a powder. MS-ESI    (M+H)⁺=449.2.

Example 305(cis,trans)-3-Dimethylmino-2-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-(N-hydroxy)cyclohexylcarboxamidebis-trifluoroacetate salt

-   (305a) Compound 304g (160 mg) was treated with TFA (1 mL)/CH₂Cl₂ (3    mL) for 20 min and the solution was concentrated on a rotary    evaporator. MS-ESI (M+H)⁺=434.2.-   (305b) To a solution of 305a (50 mg, 0.075 mmol) in THF (2 mL) was    added formaldehyde (37% aqueous solution, 0.04 mL, 0.42 mmol)    followed by N-methylmorpholine (40 mg, 0.4 mmol) and NaBH₃CN (24 mg,    0.4 mmol). After stirring at room temperature for 1 hour, the    mixture was purified on reversed phase HPLC to provide the    dimethylamino product (48 mg, 92%) as a powder. MS-ESI (M+H)⁺=462.2.-   (305c) Coupling of 305b with hydroxylamine hydrochloride using a    procedure similar to that described in (304h) provided the    hydroxamic acid as a powder. MS-ESI (M+H)⁺=477.3.

Example 306(cis,trans)-3-(1-Methyl-1-ethylmino)-2-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-(N-hydroxy)cyclohexylcarboxamidebis-trifluoroacetate salt

-   (306a) To a solution of compound 305a (52 mg, 0.08 mmol) in THF (2    mL) was added acetone (0.1 mL) followed by N-methylmorpholine (40    mg, 0.4 mmol) and Na(OAc)₃BH (25 mg, 0.12 mmol). The mixture was    stirred at room temperature overnight. Concentration on a rotary    evaporator followed by purification on reversed phase HPLC provided    the desired product (45 mg, 80%) as a powder. MS-ESI (M+H)⁺=476.2.-   (306b) Coupling of 306a with hydroxylamine hydrochloride using a    procedure similar to that described in (304h) provided the    hydroxamic acid as a powder. MS-ESI (M+H)⁺=491.3.

Example 307(cis,trans)-3-Methylamino-2-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-(N-hydroxy)cyclohexylcarboxamidebis-trifluoroacetate salt

-   (307a) To a solution of compound 304d (0.166 g, 0.39 mmol) and    benzaldehyde (0.042 g, 0.4 mmol) in THF (5 mL) was added Na(OAc)₃BH    (0.1 g, 0.5 mmol). The mixture was stirred for 1 hour at room    temperature. The product formed was a bis-benzylated product. More    benzaldehyde (0.042 g, 0.4 mmol) and Na(OAc)₃BH were added. The    mixture was stirred for another hour and purified on reversed phase    HPLC to provide the bis-benzylated product (0.15 g, 78%) as a    powder. MS-ESI (M+H)⁺=487.3.-   (307b) Compound 307a (0.15 g, 0.3 mmol) was dissolved in MeOH (10    mL) and 10% Pd—C (30 mg) was added. The mixture was hydrogenated at    atmospheric pressure for 3 hours. The catalyst was filtered off and    the filtrate was concentrated on a rotary evaporator. Purification    on reversed phase HPLC provided the mono-benzylated product (114 mg,    75%) as a powder. MS-ESI (M+H)⁺=397.2.-   (307c) To a solution of 307b (81 mg, 0.16 mmol) and Na(OAc)₃BH (20    g, 0.32 mmol) in THF (2 mL) was added N-methylmorpholine (40 mg, 0.4    mmol) followed by formaldehyde (37% aqueous solution, 25 mg, 0.3    mmol). The mixture was stirred for 1 hour and concentrated on a    rotary evaporator. Chromatography on a silica gel column (10%    MeOH/CH₂Cl₂) provided the N-benzyl-N-methyl product (60 mg, 94%)-as    a solid. MS-ESI (M+H)⁺=411.2.-   (307d) Compound 307c (60 mg, 0.15 mmol) was dissolved in EtOH (5 mL)    in a Parr bottle and to it was added 4 N HCl in dioxane (0.1 mL)    followed by 10% Pd—C (10 mg). The mixture was hydrogenated on a Parr    shaker at 50 psi for 4 hours. The catalyst was filtered off and the    filtrate was concentrated on a rotary evaporator to provide the    methylamino product as a solid. MS-ESI (M+H)⁺=321.2.-   (307e) To a solution of 307d (46 mg, 0.13 mmol) in THF (4    mL)/saturated aqueous NaHCO₃ solution (1 mL) cooled in an ice bath    was added 1 N NaOH (0.13 mL) followed by di-tert-butyl-dicarbonate    (28 mg, 0.13 mmol). The mixture was stirred at room temperature    overnight. EtOAc (50 mL) was added and the solution was washed with    brine (2×20 mL), dried (MgSO₄) and concentrated on a rotary    evaporator. MS-ESI (M+H)⁺=421.1.-   (307f) A mixture of the crude product 307e,    4-chloromethyl-2-methylquinoline (30 mg, 0.13 mmol), K₂CO₃ (138 mg,    1 mmol) and Bu₄NI (20 mg, 0.13 mmol) in DMF (2 mL) was heated at    60° C. for 5 hours. Purification using reversed phase HPLC provided    the desired product (68 mg, 90%) as a powder. MS-ESI (M+H)⁺=576.3.-   (307g) The final product was obtained by saponification of the ethyl    ester 307f followed by acid deprotection of the Boc group using    procedures similar to those described in (304g)-(304i). MS-ESI    (M+H)⁺=463.2.

Example 308(cis,cis)-3-Hydroxy-2-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-(N-hydroxy)cyclohexylcarboxamidetrifluoroacetate salt

-   -   This compound was obtained by saponification of the ethyl ester        intermediate 301c followed by coupling the resulting carboxylic        acid with hydroxylamine hydrochloride using procedures similar        to those described in (304g) and (304h). MS-ESI (M+H)⁺=450.2.

Example 309N-{cis-2-[(Hydroxyamino)carbonyl]cyclopentyl}-4-{[(2-methyl-4-quinolinyl)methyl]amino}benzamide

-   (309a) A mixture of methyl 4-aminobenzoate (1.51 g, 10 mmol),    4-chloromethyl-2-methylquinoline hydrochloride (2.28 g, 10 mmol) and    K₂CO₃ (3.2 g, 25 mmol) in DMF (20 mL) was stirred at 100° C.    overnight. EtOAc (200 mL) was added. The solution was washed with    water 2×, brine 2×, dried (MgSO₄) and concentrated. Flash    chromatography on silica eluting with EtOAc/hexanes (2:1) provided    the desired product (600 mg, 20%). MS m/z 307.1 (M+H)⁺.-   (309b) To a solution of 309a (400 mg, 1.3 mmol) in MeOH (5 mL) and    THF (5 mL) was added 1 N KOH (5 mL). The solution was stirred at    80° C. for 3 h and concentrated. The residue was taken up in 1 N HCl    solution (4 mL) and the solvent was removed under reduced pressure.    The resulting residue was dissolved in MeOH. Insoluble materials    were filtered off and the filtrate was concentrated to give the    desired carboxylic acid product that was used for the next reaction    without purification. MS m/z 293.2 (M+H)⁺.-   (309c) To a solution of 309b (200 mg, 0.684 mmol), ethyl    cis-2-aminocyclopentanecarboxylate hydrochloride (108 mg, 0.6 mmol)    and triethylamine (303 mg, 3 mmol) in DMF (3 mL) cooled in an ice    bath was added BOP (266 mg, 0.6 mmol). The solution was stirred at    room temperature for 2 h. Purification by reversed phase HPLC    provided the desired product (130 mg, 34%) as a    bis-trifluoroacetate. MS m/z 418.2 (M+H)⁺.-   (309d) Compound 309c (120 mg, 0.186 mmol) was dissolved in a 1.7 M    hydroxylamine solution (3 mL). The reaction was stirred at room    temperature for 20 min and quenched with a solution of 4 N HCl in    dioxane (0.5 mL). The solvents were removed under reduced pressure    and the residue was purified by reversed phase HPLC to give the    desired product (90 mg, 75%) as a powder. MS m/z 419.1 (M+H)⁺.

Example 310N-{cis-2-[(Hydroxyamino)carbonyl]cyclopentyl}-4-{methyl[(2-methyl-4-quinolinyl)methyl]amino}benzamide

-   (310a) This compound was prepared using procedures analogous to    those described for Example 309. MS m/z 433.2 (M+H)⁺.

Example 311N-{cis-2-[(Hydroxyamino)carbonyl]cyclopentyl}-4-(3-phenyl-4,5-dihydro-5-isoxazolyl)benzamide

-   (311a) To a stirred solution of benzaldehyde oxime (605 mg, 5 mmol)    and methyl 4-vinylbenzoate (810 mg, 5 mmol) in CH₂Cl₂ (20 mL) was    added a bleach solution (30 mL). The mixture was stirred at room    temperature for 4 h and diluted with CH₂Cl₂. The organic phase was    separated, washed with brine 2×, dried (MgSO₄) and concentrated.    Chromatography on a silica gel column eluting with EtOAc/hexanes    (1:2) provided the desired product (500 mg, 36%) as a solid. MS m/z    323.2 (M+H)⁺.-   (311b) To a solution of 3a (500 mg, 1.78 mmol) in THF (10 mL) was    added 1 N KOH (5 mL). The solution was stirred at room temperature    overnight and acidified with 1 N HCl to pH=3. The resulting solution    was extracted with EtOAc 2×. The combined organic phase was washed    with brine 2×, dried (MgSO₄) and concentrated to give the desired    acid (400 mg, 84%). MS m/z 268.2 (M+H)⁺.-   (311c) To a solution of 3b (133 mg, 0.5 mmol), ethyl    cis-2-aminocyclopentanecarboxylate hydrochloride (116 mg, 0.6 mmol)    and triethylamine (303 mg, 3 mmol) in DMF (3 mL) cooled in an ice    bath was added BOP (253 mg, 0.6 mmol). The solution was stirred at    room temperature for 2 h. Purification by reversed phase HPLC    provided the desired product (170 mg, 84%) as a powder. MS m/z 407.1    (M+H)⁺.-   (311d) Compound 3c (170 mg, 0.41 mmol) was dissolved in a 1.7 M    hydroxylamine solution (3 mL). After stirring at room temperature    for 20 min, a solution of TFA (0.3 mL) in CH₂Cl₂ (2 mL) was added    slowly. The solvents were removed under reduced pressure and the    residue was purified by reversed phase HPLC to give the desired    product (90 mg, 56%) as a powder. MS m/z 394.1 (M+H)⁺.

Example 312N-{cis-2-[(Hydroxyamino)carbonyl]cyclopentyl}-4-[3-(4-pyridinyl)-4,5-dihydro-5-isoxazolyl]benzamide

-   (312a) This compound was prepared using procedures analogous to    those described for Example 311. MS m/z 395.1 (M+H)⁺.

Example 313N-{cis-2-[(Hydroxyamino)carbonyl]cyclopentyl}-4-[3-(3-pyridinyl)-4,5-dihydro-5-isoxazolyl]benzamide

-   (313a) This compound was prepared using procedures analogous to    those described for Example 311. MS m/z 395.2 (M+H)⁺.

Example 314N-{cis-2-[(Hydroxyamino)carbonyl]cyclopentyl}-4-[3-(2-pyridinyl)-4,5-dihydro-5-isoxazolyl]benzamide

-   (314a) This compound was prepared using procedures analogous to    those described for Example 311. MS m/z 395.2 (M+H)⁺.

Example 315N-{cis-2-[(Hydroxyamino)carbonyl]cyclopentyl}-4-[3-(4-quinolinyl)-4,5-dihydro-5-isoxazolyl]benzamide

-   (315a) This compound was prepared using procedures analogous to    those described for Example 311. MS m/z 445.1 (M+H)⁺.

Example 3164-[3-(2,6-Dimethyl-4-pyridinyl)-4,5-dihydro-5-isoxazolyl]-N-{cis-2-[(hydroxyamino)carbonyl]cyclopentyl}benzamide

-   (316a) This compound was prepared using procedures analogous to    those described for Example 311. MS m/z 423.1 (M+H)⁺.

Example 317N-{cis-2-[(Hydroxyamino)carbonyl]cyclopentyl}-3-methoxy-4-[3-(4-pyridinyl)-4,5-dihydro-5-isoxazolyl]benzamide

-   (317a) This compound was prepared using procedures analogous to    those described for Example 311. MS m/z 425.1 (M+H)⁺.

Example 3183-Hydroxy-N-{cis-2-[(hydroxyamino)carbonyl]cyclopentyl}-4-[3-(4-pyridinyl)-4,5-dihydro-5-isoxazolyl]benzamide

-   (318a) This compound was prepared using procedures analogous to    those described for Example 311. MS m/z 411.1 (M+H)⁺.

Example 319N-{cis-2-[(Hydroxyamino)carbonyl]cyclopentyl}-4-[5-(2-pyridinyl)-4,5-dihydro-3-isoxazolyl]benzamide

-   (319a) To a solution of methyl 4-formylbenzoate (10 g, 61 mmol) in    MeOH (100 mL) was added hydroxylamine hydrochloride (7 g, 100 mmol)    followed by triethylamine (13.9 mL, 100 mmol). The mixture was    stirred at room temperature overnight. The solvent was removed under    reduced pressure and the residue was taken up in EtOAc (300 mL). The    solution was washed with brine 3×, dried (MgSO₄), and concentrated.    Flash chromatography on silica eluting with EtOAc/hexanes (2:1)    provided the desired oxime product (2.5 g, 23%) as a solid. MS m/z    180.1 (M+H)⁺.-   (319b) To a solution of 11a (716 mg, 4 mmol) and 2-vinylpyridine    (525 mg, 5 mmol) in CH₂Cl₂ (20 mL) was added a solution of bleach    (30 mL). The solution was stirred at room temperature overnight and    diluted with CH₂Cl₂. The organic phase was separated, washed with    brine 2×, dried (MgSO₄) and concentrated. Chromatography on a silica    gel column eluting with EtOAc/hexanes (2:1) provided the desired    product (800 mg, 73%) as a solid. MS m/z 283.2 (M+H)⁺.-   (319c) To a solution of 11b (800 mg, 2.83 mmol) in THF (5 mL) and    MeOH (3 mL) was added a solution of 1 N KOH (5 mL). The solution was    stirred at room temperature for 4 h and acidified with a solution of    1 N HCl (6 mL). The solvents were removed under reduced pressure.    The residue was dissolved in MeOH, the insoluble materials were    filtered off and the filtrate was concentrated to give the desired    carboxylic acid that was used for the next reaction without    purification. MS m/z 269.2 (M+H)⁺.-   (319d) To a solution of 11c (152 mg, 0.5 mmol), ethyl    cis-2-aminocyclopentanecarboxylic acid hydrochloride (116 mg, 0.6    mmol) and triethylamine (303 mg, 3 mmol) in DMF (3 mL) cooled in an    ice bath was added BOP (253 mg, 0.6 mmol). The solution was stirred    at room temperature for 4 h. Purification by reversed phase HPLC    provided the desired product (190 mg, 73%) as a TFA salt. MS m/z    408.1 (M+H)⁺.-   (319e) Treatment of 11d with a solution of hydroxylamine following    the procedure described in (311d) provided the desired hydroxamic    acid. MS m/z 395.1 (M+H)⁺.

Example 320N-{cis-2-[(Hydroxyamino)carbonyl]cyclopentyl}-4-[5-(4-pyridinyl)-4,5-dihydro-3-isoxazolyl]benzamide

-   (320a) This compound was prepared using procedures analogous to    those described for Example 319. MS m/z 395.1 (M+H)⁺.

Example 501N-{4-[(hydroxyamino)carbonyl]-3-pyrrolidinyl}-1-[(2-methyl-4-quinolinyl)methyl]-1H-indole-5-carboxamidebis(trifluoroacetate)

-   (501a) Indole 5-carboxylic acid (0.5 g, 3.1 mmol) was added to a    suspension of sodium hydride (0.27 g, 6.8 mmol, 60% oil dispersion)    (washed with hexanes) in DMF (20 mL) cooled to 0° C. The reaction    was allowed to stir for 1 h and the    4-chloromethyl-2-methyl-quinoline (0.72 g, 3.8 mmol) was added. The    reaction was allowed to warm to room temperature and stirred    overnight. The reaction was neutralized with 1 N HCl and extracted    with ethyl acetate. The combined organic layer was washed with    brine, dried over magnesium sulfate and concentrated to give the    1-[(2-methyl-5,8-dihydro-4-quinolinyl)methyl]-1H-indole-5-carboxylic    acid (0.68 g, 69%) as a brown residue, MS (M+H)⁺=317.-   (501b) Thionyl chloride (5 mL) was added to a suspension of the    1-[(2-methyl-5,8-dihydro-4-quinolinyl)methyl]-1H-indole-5-carboxylic    acid from step (501a) (0.67 g, 2.1 mmol) in methylene chloride (15    mL) and was heated to reflux for 2 h. The reaction was cooled to    room temperature, concentrated in vacuo to give the    1-[(2-methyl-5,8-dihydro-4-quinolinyl)methyl]-1H-indole-5-carbonyl    chloride (0.68 g, 80%) as a yellow solid.-   (501c) The 1-tert-butyl 3-methyl    4-amino-1,3-pyrrolidinedicarboxylate (0.10 g, 0.41 mmol) was    combined with the acid chloride from step (501b) (0.10 g, 0.32 mmol)    in methylene chloride (15 mL) and water saturated sodium bicarbonate    (15 mL). The reaction was stirred for 3.5 h, partitioned between    methylene chloride and water. The organic layer was washed with    brine, dried over magnesium sulfate and concentrated to give a    solid. This was purified by flash chromatography on silica gel    eluting hexane: ethyl acetate (30:60, v:v) to give the 1-tert-butyl    3-methyl    4-[({l-[(2-methyl-4-quinolinyl)methyl]-1H-indol-5-yl}carbonyl)amino]-1,3-pyrrolidinedicarboxylate    (0.120 g, 70%) as a solid, MS (M+H)⁺=543.-   (501d) TFA (2 mL) was added to a solution of the coupled product    (0.11 g, 0.2 mmol) from step (501c) in methylene chloride (3 mL) at    room temperature. The reaction was complete after stirring for 2 h    and was concentrated to give methyl    4-[({1-[(2-methyl-4-quinolinyl)methyl]-1H-indol-5-yl}carbonyl)amino]-3-pyrrolidinecarboxylate    (0.165 g, 100%) as an oil, MS (M+2H)⁺⁺=222.-   (501e) Following a procedure analogous to that used in example (1d)    for the conversion to the hydroxamic acid, but using the methyl    ester step (501d) the title compound (0.065 g. 23%) was prepared as    a white amorphous solid, MS (M+H)⁺=444.

Example 502N-{2-[(hydroxyamino)carbonyl]cyclopentyl}-1-[(2-methyl-4-quinolinyl)methyl]-1H-indole-5-carboxamidetrifluoroacetate

-   (502a) Following a procedure analogous to that used in example (501)    but using the methyl 2-aminocyclopentanecarboxylate, the title    compound (0.038 g. 32%) was prepared as a solid, MS (M+H)⁺=443.

Example 503N-hydroxy-3-({6-[(2-methyl-4-quinolinyl)methoxy]-1-naphthoyl}amino)-4-piperidinecarboxamidebis(trifluoroacetate)

-   (503a) Following a procedure analogous to that used in example (501)    but using the methyl 3-amino-4-piperidinecarboxylate and    6-hydroxy-1-naphthoic acid, the title compound (0.015 g. 39%) was    prepared as a white amorphous solid, MS (M+H)⁺=485.

Example 504N-{2-[(hydroxyamino)carbonyl]cyclopentyl}-6-[(2-methyl-4-quinolinyl)methoxy]-1-naphthamidetrifluoroacetate

-   (504a) Following a procedure analogous to that used in example (501)    but using the methyl 2-aminocyclopentanecarboxylate and    6-hydroxy-1-naphthoic acid, the title compound (0.11 g. 57%) was    prepared as a white amorphous solid, MS (M+H)⁺=470.

Example 505N-{2-[(hydroxyamino)carbonyl]cyclopentyl}-6-[(2-methyl-4-quinolinyl)methoxy]-2-naphthamidetrifluoroacetate

-   (505a) Following a procedure analogous to that used in example (501)    but using the methyl 2-aminocyclopentanecarboxylate and    6-hydroxy-2-naphthoic acid, the title compound (0.06 g. 23%) was    prepared as a white amorphous solid, MS (M+H)⁺=470.

Example 506N-{2-[(hydroxyamino)carbonyl]cyclopentyl}-6-[(2-methyl-4-quinolinyl)methoxy]-1,2,3,4-tetrahydro-1-isoquinolinecarboxamidebis(trifluoroacetate)

-   (506a) Following a procedure analogous to that used in example (501)    but using the methyl 2-aminocyclopentanecarboxylate and    2-(tert-butoxycarbonyl)-6-hydroxy-1,2,3,4-tetrahydro-1-isoquinolinecarboxylic    acid the title compound (0.050 g. 29%) was prepared as a white    amorphous solid, MS (M+H)⁺=475.

Example 507N-{2-[(hydroxyamino)carbonyl]cyclopentyl}-1-[(2-methyl-4-quinolinyl)methyl]-1H-benzimidazole-5-carboxamidetrifluoroacetate

-   (507a) Following a procedure analogous to that used in example (501)    but using the methyl 2-aminocyclopentanecarboxylate and    1H-benzimidazole-5-carboxylic acid the title compound (0.020 g. 5%)    was prepared as a white amorphous solid, MS (M+H)⁺=444.

Example 508N-{2-[(hydroxyamino)carbonyl]cyclopentyl}-1-[(2-methyl-4-quinolinyl)methyl]-1H-indole-4-carboxamidetrifluoroacetate

-   (508a) Following a procedure analogous to that used in example (501)    but using the methyl 2-aminocyclopentanecarboxylate and    1H-indole-4-carboxylic acid, the title compound (0.085 g. 56%) was    prepared as a white amorphous solid, MS (M+H)⁺=443.

Example 700(±)-cis-N-hydroxy-2-[[4-[(2-methyl-4-quinolinyl)methoxy]benzoyl]amino]-1-cycloheptanecarboxamide,trifluoroacetate

-   (700a) Chlorosulfonylisocyanate (4.80 g, 33.9 mmol) in methylene    chloride (2 mL) was added dropwise to cycloheptene in methylene    chloride (25 mL) then heated to reflux under nitrogen for 10 h. The    reaction was quenched by dropwise addition of water then extracted    with methylene chloride (2×). The combined organic layers were    washed with water (1×) and brine (1×) then dried over magnesium    sulfate. The solvent was evaporated in vacuo and the residue diluted    with ether (15 mL). The ether solution was added dropwise to a    solution of 10% sodium sulfite/ether (2:1, 75 mL) maintaining the pH    between 7 and 8 with 10% sodium hydroxide. After the addition was    complete stirring was continued for 0.5 h then the reaction was    extracted with ether (3×). The combined organic layers were washed    with water (1×) and brine (1×) then dried over magnesium sulfate.    The solvent was evaporated in vacuo to provide 700a (3.76 g, 87%) as    a waxy yellow solid. MS: APc [M+(CH₃CN+H)]+=181.-   (700b) Chlorotrimethylsilane (5.87 g, 54 mmol) was added dropwise to    700a (3.76 g, 27.0 mmol) in methanol (75 mL) at room temperature    under nitrogen. After stirring for 2 h the solvent was evaporated in    vacuo and the residue titurated with ether. The white solid was    filtered then dried under vacuum for 24 h to provide 700b (4.52 g,    81%). MS: ESI [M+H]⁺=172.-   (700c) N-Methyl morpholine (0.73 g, 7.22 mmol) was added dropwise to    700b (0.5 g, 2.41 mmol), BOP reagent (1.17 g, 2.65 mmol), and    4-[(2-methyl-4-quinolinyl)methoxy]benzoic acid (0.71 g, 2.41 mmol)    in dimethylformamide (10 mL) at 0° C. under nitrogen. The reaction    was allowed to warm to room temperature then stirred overnight. The    solvent was removed in vacuo and the residue taken up in ethyl    acetate (100 mL). The solution was washed with water (2×), saturated    sodium bicarbonate (2×), and brine (1×) then dried over magnesium    sulfate. The solvent was removed in vacuo and the residue purified    by flash chromatography (SiO₂, 75%-100% ethyl acetate/hexanes) to    provide 700c (0.963 g, 89%) as a viscous light yellow oil. MS: ESI    [M+H]⁺=447.-   (700d) A solution of basic hydroxylamine was prepared by adding    potassium hydroxide (2.81 g, 50.2 mmol) in methanol (7 mL) to    hydroxylamine hydrochloride (2.34 g, 33.7 mmol) in hot methanol (12    mL). The solution was allowed to cool to ambient temperature and the    solid potassium chloride was filtered. The hydroxylamine solution    (15 mL) was added in one portion to 700c (0.25 g, 0.56 mmol) and    stirred for 6 h. The reaction was quenched with 1N hydrogen chloride    (˜15 mL) until the pH was approximately 6. The solvent was removed    in vacuo and the residue taken up in 1N hydrogen chloride/methanol    (1:1) then purified by C₁₈ HPLC to provide example 700(88 mg, 32%).    MS: ESI [M+H]⁺=448.

Example 701(±)-trans-N-hydroxy-2-[[4-[(2-methyl-4-quinolinyl)methoxy]benzoyl]amino]-1-cycloheptanecarboxamide,trifluoroacetate

-   (701a) Diazabicyclo[5.4.0]undec-5-ene (0.39 g, 2.58 mmol) was added    to 700c (0.23 g, 0.52 mmol) in xylenes (10 mL) then heated at    100° C. for 8 h and 110° C. for 14 h. The solvent was evaporated in    vacuo and the residue purified by flash chromatography (SiO₂, 65%    ethyl acetate/hexanes) to provide 701a (103 mg, 45%) with >90%    isomeric purity. MS: ESI [M+H]⁺=447.-   (701b) Example 701 was prepared in a procedure analogous to 700d.    MS: ESI [M+H]⁺=448.

Example 702(4S,5R)-N-hydroxy-5-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-2-oxohexahydro-1H-azepine-4-carboxamidetrifluoroacetate

-   (702a) Diphenylphosphoryl azide (4.72 g, 17.1 mmol) was added    dropwise to 1-methyl (1S,2R)-(+)-cis-1,2,3,6-tetrahydrophthalate    (2.63 g, 14.3 mol) and triethylamine (2.17 g, 41.2 mmol) in benzene    (20 mL) at room temperature. After stirring for 2 h benzyl alcohol    (1.85 g, 17.1 mmol) was added and the reaction was heated to reflux    for 3 h. The mixture was cooled to room temperature and diluted with    ethyl acetate (150 mL). The solution was washed with water (1×), 10%    citric acid (1×), saturated sodium bicarbonate (1×), and brine (1×)    then dried over magnesium sulfate. The solvent was evaporated in    vacuo and the residue purified by flash chromatography (SiO₂, 20-30%    ethyl acetate/hexanes as solvent. The product 702a (2.69, 65%) was    isolated as a brittle foam. MS: ESI [M+H]⁺=290.-   (702b) Borane:tetrahydrofuran (1M, 9.66 mL, 9.66 mmol) was added    dropwise to 702a (2.15 g, 7.43 mmol) in anhydrous tetrahydrofuran    (20 mL) at 0° C. under nitrogen. The reaction was allowed to warm to    room temperature over 1.5 h then cooled again to 0° C. and quenched    by the dropwise addition of a with of 30% hydrogen peroxide (4.5 mL)    and 1N sodium hydroxide (10 mL). After the addition was completed    the mixture was stirred 15 m then quenched with 10% sodium sulfite.    The solution was extracted with ethyl acetate (3×) and the combined    organic extracts were washed with 10% sodium sulfite (2×) and brine    (1×). After drying over magnesium sulfate the solvent was removed in    vacuo and the product 702b (2.35 g, 100%) was carried forward    without further purification. MS: APc [M+H]⁺=308.-   (702c) Pyridinium dichromate (4.19 g. 11.1 mmol) was added in one    portion to 702b(7.43 mmol) and powdered 3 A molecular sieves (5 g)    in methylene chloride (30 mL) then stirred for 3 h at ambient    temperature. The reaction was filtered through celite under vacuum    washing with methylene chloride. The solvent was evaporated in vacuo    and the residue purified by flash chromatography (SiO₂, 50% ethyl    acetate/hexanes) to provide 702c (1.68 g, 74%) as a viscous light    yellow oil. MS: APc [M+H]⁺=306.-   (702d) Hydroxylamine hydrochloride (1.53 g, 22.0 mmol) was added in    one portion to 702c (1.68 g, 5.50 mmol) and sodium bicarbonate (1.53    g, 18.2 mmol) in methanol (25 mL) then heated to reflux for 3 h. The    mixture was cooled to ambient temperature then diluted with water    (50 mL) and extracted with chloroform (4×). The combined organic    extracts were washed with brine (1×) then dried over magnesium    sulfate. The solvent was evaporated in vacuo and the residue    purified by flash chromatography (SiO₂, 50% ethyl acetate/hexanes)    to provide 702d (1.46 g, 83%) as a viscous light yellow oil. MS: ESI    [M+H]⁺=321.-   (702e) 702d(1.46 g, 4.56 mmol) in methylene chloride (10 mL) was    added dropwise to p-toluenesulfonyl chloride (1.04 g, 5.47 mmol) and    pyridine (0.54 g, 6.84 mmol) in methylene chloride (20 mL) at room    temperature. The reaction was stirred for 14 h then diluted with    methylene chloride (80 mL). The solution was washed with 1N    hydrochloric acid (2×), saturated sodium bicarbonate (2×), and brine    (1×) then dried over magnesium sulfate. The solvent was evaporated    in vacuo and the tosylate ([M+H]⁺=475) was taken up in ethanol free    chloroform (40 mL) and added to dry silica gel (20 g). The reaction    was stirred for 4 h then poured onto the top of a flash column    (SiO₂, 80 g, 50% ethyl acetate hexanes to 50% methanol/ethyl    acetate) and eluted. The mixture of four regioisomeric lactams were    purified by C₁₈ HPLC (CH₃CN/water, 0.1% trifluoroacetic acid) to    provide 702e-a, 702e-b, 702e-c, and 702e-d (410 mg, 267 mg, 364, mg,    195 mg, respectively, 85%). MS: APc [M+H]⁺=321 for all samples.-   (702f) Methanol (10 mL) was carefully added to 10% Pd on C (0.17 g)    and 702e-c (264 mg, 1.14 mmol) under a bed of nitrogen. A hydrogen    balloon was attached via a three-way stopcock and the atmosphere was    removed and replaced with hydrogen three times. After 0.5 h the    hydrogen was removed and replaced with nitrogen then the catalyst    removed by vacuum. filtration through celite. The solvent was    removed in vacuo to provide 702f (239 mg, 100%) as a viscous oil.    MS: ESI [M+H]⁺=187.-   (702g) In a procedure analogous to 700c, 702f was coupled to    4-[(2-methyl-4-quinolinyl)methoxy]benzoic acid to provide 702g (0.28    g, 53%)as a viscous clear oil. MS: ESI [M+H]⁺=462.-   (702h) In a procedure analogous to 700d, 702g was converted to the    hydroxamic acid example 702 were the regiochemistry was proven by 2D    ¹HNMR. MS: ESI [M+H]⁺=463.

Example 703 and Example 704(3S,4S)-N-hydroxy-3-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-7-oxohexahydro-1H-azepine-4-carboxamidetrifluoroacetate and(3S,4R)-N-hydroxy-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-7-oxohexahydro-1H-azepine-3-carboxamidetrifluoroacetate and(4S,5R)-N-hydroxy-5-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-7-oxohexahydro-1H-azepine-4-carboxamidetrifluoroacetate

-   (703a) In a series of procedures analogous to steps 702f through    702h, 702e-a was converted to example 703. (704) In a series of    procedures analogous to steps 702f through 702h 702e-b was converted    example 704.

Example 705 and Example 706(2S,3R)-N-hydroxy-3-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-2-pyrrolidinecarboxamideditrifluoroacetate and(2R,3R)-N-hydroxy-3-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-2-pyrrolidinecarboxamideditrifluoroacetate

-   (705a,706a) Di-t-butyl dicarbonate (8.60 g, 39.4 mmol) in    tetrahydrofuran (20 mL) was added dropwise to    trans-3-hydroxy-L-proline (5.16 g, 39.4 mmol) in mixture of 1N    sodium hydroxide (43.3 mL) and tetrahydrofuran (20 mL) at ambient    temperature. The solution was stirred overnight then extracted with    pet ether (2×). The pet ether extracts were washed with saturated    sodium bicarbonate (3×) then the combined aqueous layers were    carefully acidified with sodium hydrogensulfate monohydate. The    aqueous solution was extracted with ethyl acetate (3×) and the    combined organic layers were dried over magnesium sulfate. The    solvent was removed in vacuo to give 706a/707a (8.29 g, 91%). MS:    ESI⁻[M−H]⁻=230.-   (705b,706b) N-Methyl morpholine (7.25 g, 71.7 mmol) was added in a    slow stream to 705a,706a (8.29 g, 35.8 mmol), BOP reagent (17.4 g,    39.4 mmol), and N-benzylhydroxylamine hydrochloride (7.44 g, 46.6    mmol) in dimethylformamide (75 mL) under nitrogen. The reaction was    stirred overnight and the solvent was evaporated in vacuo. The    residue was taken up in ethyl acetate (300 mL) and washed with water    (2×), 10% citric acid (2×), saturated sodium bicarbonate (2×), and    brine (1×) then dried over magnesium sulfate. The solvent was    removed in vacuo and the residue purified by flash chromatography    (SiO₂, 50%-80% ethyl acetate/hexanes) to provide 706b,707b(6.11 g,    51%) as a viscous oil. MS: ESI [M+H]⁺=337.-   (705c,706c) Diazoethyldicarboxylate (3.16 g, 18.2 mmol) was added    dropwise to 705b,706b (6.11 g, 18.2 mmol) and triphenylphosphine    (5.24 g, 20.0 mmol) in anhydrous tetrahydrofuran (50 mL) at room    temperature under nitrogen. After stirring overnight the solvent was    evaporated in vacuo and the residue purified by flash chromatography    (SiO₂, 20%-30% ethyl acetate/hexanes) to provide 706c,707c (4.61 g,    80%). MS: APc [M+H]⁺=319.-   (705d,706d) Methanol (75 mL) was carefully added to 705c,706c(4.61    g, 14.5 mmol) and Pd on C(10%, 1.3 g) under a bed of nitrogen. A    hydrogen balloon was attached via a 3-way stopcock and the    atmosphere was removed and replace with hydrogen three times. After    1.5 h the hydrogen was removed and the reaction was vented with    nitrogen. The catalyst was removed by vacuum filtration through    celite and the sovent was removed in vacuo to provide 706d,707d    (3.09 g, 93%). MS: APc {M+H]⁺=229.-   (705e,706e) Sodium acetate (23.8 g, 290 mmol) was added to 705d,706d    (3.09 g, 13.5 mmol) in water/tetrahydrofuran (200 mL, 1/1) at room    temperature. Titanium trichloride (36.7 g, 12 wt % in 21% HCl(aq),    29.0 mmol) was added dropwise and stirring was continued for 3 h at    room temperature. The reaction mixture was extracted with ethyl    acetate (1×) then titanium dioxide was removed from the aqueous    layer by vacuum filtration through celite. The aqueous layer was    extracted again with ethyl acetate (2×) and the combined ethyl    acetate layers were washed with brine (1×). The solvent was removed    in vacuo and the resulting solid was recrystallized from ethyl    acetate/hexanes to provide 706e,707e (1.64 g, 57%). MS: CI    [(M−C₄H₈)+H]⁺=157.-   (705f,706f) Chlorotrimethylsilane (256 mg, 2.36 mmol) was added    dropwise to 705e,706e (250 mg, 1.18 mmol) in methanol (2 mL) at room    temperature under nitrogen. After stirring for 2 h the solvent was    evaporated in vacuo and the residue titurated with ether. The white    solid was filtered then dried under vacuum for 24 h to provide an    inseparable mixture of Boc protected β-amino acid and Boc    deprotected β-amino acid 706f,707f (235 mg) that was taken forward    without further purification. MS: CI [(M−NH₃)+H]⁺=128.-   (705g,706g) In a procedure analogous to 700c, 705f,706f (281 mg) was    coupled to 4-[(2-methyl-4-quinolinyl)methoxy]benzoic acid to provide    706g,707g-a(Boc deprotected, 78 mg, MS ESI: [M+H]⁺=420) and    706g,707g-b (Boc protected, 29 mg, [M+H]⁺=520).-   (705h,706h) Examples 706 and 707 were prepared from 705g,706g-a    using a procedure analogous to 700d. Example 707 was the first off    the C₁₈ HPLC column(MS: ESI [M+H]⁺=421) and example 706 was the    first(MS: ESI [M+H]⁺=421).

Example 707 tert-butyl(2S,3R)-2-[(hydroxyamino)carbonyl]-3-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-1-pyrrolidinecarboxylatetrifluoroacetate

-   (707a) Example 707 was prepared from 705g,705g-b using a procedure    analogous to 700d. Example 708 was isolated as a single    diastereomer. MS: ESI [M+H]⁺=521.

TABLE 1

MS [M + Ex R R² H] 1 4-(2-trifluoromethylphenyl) — 393 benzoyl 24-(2-trifluoromethylphenoxy) — 409 benzoyl 3 4-(3-methyl-2- — 340pyridinyl)benzoyl 4 4-phenylbenzoyl — 325 5 4-phenoxybenzoyl — 341 64-benzyloxybenzoyl — 355 7 4-(2-methoxyphenyl)benzoyl — 355 84-(2-methylphenyl)benzoyl — 339 9 4-(2-methoxyphenoxy)benzoyl — 371 104-(2-methylphenoxy)benzoyl — 355 11 4-(3-methylphenyl)benzoyl — 339 124-(4-quinolinyl)benzoyl — 376 13 4-(3,5- — 353 dimethylphenyl)benzoyl 145-[2-(2-methylphenyl)] — 340 pyridinylcarbonyl 155-[2-(2-methoxyphenyl)] — 356 pyridinylcarbonyl 16 4-(2-methyl-4-Isopropyl 463 quinolinylmethoxy)benzoyl 17 4-(2-methyl-4- 2,2- 505quinolinylmethoxy)benzoyl dimethylpropionyl 18 4-(2-methyl-4-methanesulfonyl 499 quinolinylmethoxy)benzoyl 19 4-(2-methyl-4- Methyl435 quinolinylmethoxy)benzoyl 20 4-(2-methyl-4- (1,1-dimethyl- 521quinolinylmethoxy)benzoyl ethoxy)carbonyl 21 4-(2-methyl-4- H 421quinolinylmethoxy)benzoyl 22 4-(2-methyl-4- 4-[N-(1,1- 604quinolinylmethoxy)benzoyl dimethyl- ethoxy)carbonyl] piperidinyl 234-(2-methyl-4- 4-piperidinyl 504 quinolinylmethoxy)benzoyl 244-(2-methyl-4- 3-[N-(1,1- 590 quinolinylmethoxy)benzoyl dimethyl-ethoxy)carbonyl] pyrrolidinyl 25 4-(2-methyl-4- pyrrolidinyl 490quinolinylmethoxy)benzoyl 26 4-(2-methyl-4- (1,1-dimethyl- 521quinolinylmethoxy)benzoyl ethoxy)carbonyl 27 4-(2-methyl-4-(1,1-dimethyl- 521 quinolinylmethoxy)benzoyl ethoxy)carbonyl 284-(2-methyl-4- H 421 quinolinylmethoxy)benzoyl 29 4-(2-methyl-4-(1,1-dimethyl- 521 quinolinylmethoxy)benzoyl ethoxy)carbonyl 304-(2-methyl-4- H 421 quinolinylmethoxy)benzoyl 31 4-(4-pyridinyl)benzoyl— 326 32 4-(2-methyl-4- 1,1-dimethyl-2- 487 quinolinylmethoxy)benzoylpropynyl 33 4-(2-methyl-4- 2-propynyl 459 quinolinylmethoxy)benzoyl 344-(2-methyl-4- 2-propenyl 461 quinolinylmethoxy)benzoyl 354-(2-methyl-4- propyl 463 quinolinylmethoxy)benzoyl 36 4-(2-methyl-4-2-methyl-2- 475 quinolinylmethoxy)benzoyl propenyl 37 4-(2-methyl-4-1,1-dimethyl-2- 489 quinolinylmethoxy)benzoyl propenyl 38 4-(2-methyl-4-1,1-dimethylpropyl 491 quinolinylmethoxy)benzoyl 39 4-(2-methyl-4-3-methylbutyl 491 quinolinylmethoxy)benzoyl 40 4-(2-methyl-4-2,2-dimethylpropyl 491 quinolinylmethoxy)benzoyl 41 4-(2-methyl-4- butyl477 quinolinylmethoxy)benzoyl 42 4-(2-methyl-4- 3-butenyl 475quinolinylmethoxy)benzoyl 43 4-(2-methyl-4- 2-butynyl 473quinolinylmethoxy)benzoyl 44 4-(2-methyl-4- 2-furylmethyl 501quinolinylmethoxy)benzoyl 45 4-(2-methyl-4- (5-methyl-2- 515quinolinylmethoxy)benzoyl furyl)methyl 46 4-(2-methyl-4- — 422quinolinylmethoxy)benzoyl 47 4-(2-methyl-4- — 422quinolinylmethoxy)benzoyl 48 4-(2-methyl-4- 1,3-thiazol-2- 518quinolinylmethoxy)benzoyl ylmethyl 49 4-(2-methyl-4- acetyl 463quinolinylmethoxy)benzoyl 50 4-(2-methyl-4- isobutyryl 491quinolinylmethoxy)benzoyl 51 4-(2-methyl-4- 3-methylbutanoyl 505quinolinylmethoxy)benzoyl 52 4-(2-methyl-4- cyclopropylcarbonyl 489quinolinylmethoxy)benzoyl 53 4-(2-methyl-4- cyclobutylcarbonyl 503quinolinylmethoxy)benzoyl 54 4-(2-methyl-4- methoxyacetyl 493quinolinylmethoxy)benzoyl 55 4-(2-methyl-4- 2-furoyl 515quinolinylmethoxy)benzoyl 56 4-(2-methyl-4- 2-thienylcarbonyl 531quinolinylmethoxy)benzoyl 57 4-(2-methyl-4- propionyl 477quinolinylmethoxy)benzoyl 58 4-(2-butynyloxy)benzoyl — 319 594-(2-methyl-4- — 434 quinolinylmethoxy)benzoyl 60 4-(2-methyl-4- OH 436quinolinylmethoxy)benzoyl 61 4-(2-methyl-4- OH 436quinolinylmethoxy)benzoyl 62 4-(2-methyl-4- tetrahydro-2H- 505quinolinylmethoxy)benzoyl pyran-4-yl 63 4-(2-methyl-4- methoxycarbonyl479 quinolinylmethoxy)benzoyl 64 4-(2-methyl-4- ethoxycarbonyl 493quinolinylmethoxy)benzoyl 65 4-(2-methyl-4- propyloxycarbonyl 507quinolinylmethoxy)benzoyl 66 4-(2-methyl-4- 2- 505quinolinylmethoxy)benzoyl propenyloxycarbonyl 67 4-(2-methyl-4-isopropyloxycarbonyl 507 quinolinylmethoxy)benzoyl 68 4-(2-methyl-4- 2-503 quinolinylmethoxy)benzoyl propynyloxycarbonyl 69 4-(2-methyl-4- 2-517 quinolinylmethoxy)benzoyl butynyloxycarbonyl 70 4-(2-methyl-4- 3-519 quinolinylmethoxy)benzoyl butenyloxycarbonyl 71 4-(2-methyl-4-benzyloxycarbonyl 554 quinolinylmethoxy)benzoyl 72 4-(2-methyl-4-dimethylamino 463 quinolinylmethoxy)benzoyl 73 4-(2-butynyloxy)benzoylisopropyl 360 74 4-(2-methyl-4- — 456 quinolinylmethoxy)benzoyl 754-(2-methylphenoxy)benzoyl isopropyl 398 100 4-(2-methyl-4- — 420quinolinylmethoxy)benzoyl 101 4-(2-methyl-4- — 420quinolinylmethoxy)benzoyl 102 4-(2-methyl-4- — 420quinolinylmethoxy)benzoyl 103 4-(2-methyl-4- — 420quinolinylmethoxy)benzoyl 104 4-(2-methyl-4- — 434quinolinylmethoxy)benzoyl 105 4-(2-methyl-4- — 434quinolinylmethoxy)benzoyl 108 4-(2-methyl-4- (1,1-dimethyl- 521quinolinylmethoxy)benzoyl ethoxy)carbonyl 109 4-(2-methyl-4- H 421quinolinylmethoxy)benzoyl 110 4-(2-methyl-4- (1,1-dimethyl- 521quinolinylmethoxy)benzoyl ethoxy)carbonyl 111 4-(2-methyl-4- H 421quinolinylmethoxy)benzoyl 112 4-(2-methyl-4- (1,1-dimethyl- 535quinolinylmethoxy)benzoyl ethoxy)carbonyl 113 4-(2-methyl-4-(1,1-dimethyl- 535 quinolinylmethoxy)benzoyl ethoxy)carbonyl 1144-(2-methyl-4- H 435 quinolinylmethoxy)benzoyl 115 4-(2-methyl-4- H 435quinolinylmethoxy)benzoyl 116 4-(2-methyl-4- butoxycarbonyl 535quinolinylmethoxy)benzoyl 117 4-(2-methyl-4- (1-methyl- 521quinolinylmethoxy)benzoyl ethoxy)carbonyl 118 4-(2-methyl-4-methanesulfonyl 513 quinolinylmethoxy)benzoyl 119 4-(2-methyl-4-benzenesulfonyl 575 quinolinylmethoxy)benzoyl 120 4-(2-methyl-4- acetyl477 quinolinylmethoxy)benzoyl 121 4-(2-methyl-4- benzoyl 539quinolinylmethoxy)benzoyl 122 4-(2-methyl-4- 2,2- 519quinolinylmethoxy)benzoyl dimethylpropionyl 123 4-(2-methyl-4- 3,3- 533quinolinylmethoxy)benzoyl dimethylbutanoyl 124 4-(2-methyl-4- 4- 548quinolinylmethoxy)benzoyl morpholinecarbonyl 125 4-(2-methyl-4-dimethylcarbamyl 506 quinolinylmethoxy)benzoyl 126 4-(2-methyl-4- methyl449 quinolinylmethoxy)benzoyl 127 4-(2-methyl-4- ethyl 463quinolinylmethoxy)benzoyl 128 4-(2-methyl-4- n-propyl 477quinolinylmethoxy)benzoyl 129 4-(2-methyl-4- isopropyl 477quinolinylmethoxy)benzoyl 130 4-(2-methyl-4- cyclopropylmethyl 489quinolinylmethoxy)benzoyl 131 4-(2-methyl-4- 2,2-dimethylpropyl 505quinolinylmethoxy)benzoyl 132 4-(2-methyl-4- benzyl 525quinolinylmethoxy)benzoyl 133 4-(2-methyl-4- 2-thiazolylmethyl 532quinolinylmethoxy)benzoyl 134 4-(2-methyl-4- (1,1-dimethyl- 535quinolinylmethoxy)benzoyl ethoxy)carbonyl 135 4-(2-methyl-4-(1,1-dimethyl- 535 quinolinylmethoxy)benzoyl ethoxy)carbonyl 1364-(2-methyl-4- H 435 quinolinylmethoxy)benzoyl 137 4-(2-methyl-4- H 435quinolinylmethoxy)benzoyl 138 4-(2-methyl-4- (2-ethyl- 535quinolinylmethoxy)benzoyl propyloxy)carbonyl 139 4-(2-methyl-4-methoxycarbonyl 493 quinolinylmethoxy)benzoyl 140 4-(2-methyl-4-(1-methyl- 521 quinolinylmethoxy)benzoyl ethoxy)carbonyl 1414-(2-methyl-4- methanesulfonyl 513 quinolinylmethoxy)benzoyl 1424-(2-methyl-4- benzenesulfonyl 575 quinolinylmethoxy)benzoyl 1474-(2-methyl-4- 3,3- 533 quinolinylmethoxy)benzoyl dimethylbutanoyl 1484-(2-methyl-4- 2,2- 519 quinolinylmethoxy)benzoyl dimethylpropionyl 1494-(2-methyl-4- benzoyl 539 quinolinylmethoxy)benzoyl 150 4-(2-methyl-4-nicotinoyl 540 quinolinylmethoxy)benzoyl 151 4-(2-methyl-4- 2- 545quinolinylmethoxy)benzoyl thiophenecarbonyl 152 4-(2-methyl-4-dimethylcarbamyl 506 quinolinylmethoxy)benzoyl 153 4-(2-methyl-4- 4- 548quinolinylmethoxy)benzoyl morpholinecarbonyl 154 4-(2-methyl-4-[2-(2-thienyl) 588 quinolinylmethoxy)benzoyl ethyl]carbamyl 1554-(2-methyl-4- (1,1-dimethyl- 534 quinolinylmethoxy)benzoylethyl)carbamyl 156 4-(2-methyl-4- Methyl 449 quinolinylmethoxy)benzoyl157 4-(2-methyl-4- Ethyl 463 quinolinylmethoxy)benzoyl 1584-(2-methyl-4- n-propyl 477 quinolinylmethoxy)benzoyl 159 4-(2-methyl-4-isopropyl 477 quinolinylmethoxy)benzoyl 160 4-(2-methyl-4- cyclobutyl489 quinolinylmethoxy)benzoyl 161 4-(2-methyl-4- n-butyl 491quinolinylmethoxy)benzoyl 162 4-(2-methyl-4- 2-methylpropyl 491quinolinylmethoxy)benzoyl 163 4-(2-methyl-4- cyclopropylmethyl 489quinolinylmethoxy)benzoyl 164 4-(2-methyl-4- 2,2-dimethylpropyl 505quinolinylmethoxy)benzoyl 165 4-(2-methyl-4- cyclopentyl 503quinolinylmethoxy)benzoyl 166 4-(2-methyl-4- 4- 519quinolinylmethoxy)benzoyl tetrahydropyranyl 167 4-(2-methyl-4- Benzyl525 quinolinylmethoxy)benzoyl 168 4-(2-methyl-4- 2-thiazolylmethyl 532quinolinylmethoxy)benzoyl 169 4-(2-methyl-4- 4-picolyl 526quinolinylmethoxy)benzoyl 170 4-(2-methyl-4- 2-picolyl 526quinolinylmethoxy)benzoyl 171 4-(2-methyl-4- 3-picolyl 526quinolinylmethoxy)benzoyl 172 4-(2-methyl-4- Trans-cinnamyl 551quinolinylmethoxy)benzoyl 173 4-(2-methyl-4- Phenyl 511quinolinylmethoxy)benzoyl 174 4-(2-methyl-4- Pivolyl 519quinolinylmethoxy)benzoyl 175 4-(2-methyl-4- Methyl 449quinolinylmethoxy)benzoyl 176 4-(2-methyl-4- dimethylcarbamyl 506quinolinylmethoxy)benzoyl 177 4-(2-methyl-4- n-hexyl 519quinolinylmethoxy)benzoyl 178 4-(2-methyl-4- 2-fluoroethyl 481quinolinylmethoxy)benzoyl 179 4-(2-methyl-4- 2,2-difluoroethyl 499quinolinylmethoxy)benzoyl 180 4-(2-methyl-4- 1-methylpropyl 491quinolinylmethoxy)benzoyl 181 4-(2-methyl-4- 2-ethylpropyl 505quinolinylmethoxy)benzoyl 182 4-(2-methyl-4- 4-[N-(1,1- 618quinolinylmethoxy)benzoyl dimethyl- ethoxy)carbonyl] piperidinyl 1834-(2-methyl-4- 4-piperidinyl 518 quinolinylmethoxy)benzoyl 1844-(2-methyl-4- 3-[N-(1,1- 604 quinolinylmethoxy)benzoyl dimethyl-ethoxy)carbonyl] pyrrolidinyl 185 4-(2-methyl-4- Pyrrolidinyl 505quinolinylmethoxy)benzoyl 186 4-(2-methyl-4- 1,1-dimethyl-2- 501quinolinylmethoxy)benzoyl propynyl 187 4-(2-methyl-4- (3- 531quinolinylmethoxy)benzoyl thiophenyl)methyl 188 4-(2-methyl-4- Isopropyl493 quinolinylmethoxy)benzoyl 189 4-(2-methyl-1-oxo-4- Isopropyl 493quinolinylmethoxy)benzoyl 190 4-(2-methyl-1-oxo-4- Isopropyl 509quinolinylmethoxy)benzoyl 191 4-(2-methyl-4- 2-oxo-2-(4- 562quinolinylmethoxy)benzoyl morpholinyl)ethyl 192 4-(2-methyl-4-2-dimethylamino-2- 520 quinolinylmethoxy)benzoyl oxoethyl 1934-(2-methyl-4- t-butylsulfonyl 555 quinolinylmethoxy)benzoyl 1944-(2-methyl-1-oxo-4- t-butylsulfonyl 571 quinolinylmethoxy)benzoyl 1954-(2-methyl-4- Benzenesulfonyl 575 quinolinylmethoxy)benzoyl 1964-(2-methyl-4- t-butylsulfinyl 539 quinolinylmethoxy)benzoyl 1974-(2-methyl-4- 2-hydroxylethyl 479 quinolinylmethoxy)benzoyl 1984-(2-methyl-4- 2-[(1,1-dimethyl- 578 quinolinylmethoxy)benzoylethoxy)carbonyl] aminoethyl 199 4-(2-methyl-4- 2-aminoethyl 478quinolinylmethoxy)benzoyl 200 4-(2-methyl-4- 2-(N,N- 506quinolinylmethoxy)benzoyl dimethylamino) ethyl 201 4-(2-methyl-4-2-aminopropyl 492 quinolinylmethoxy)benzoyl 202 4-(2-methyl-4-2-amino-3- 508 quinolinylmethoxy)benzoyl hydroxypropyl 2034-(2-methyl-4- (2- 518 quinolinylmethoxy)benzoyl pyrrolidinyl)methyl 2044-(2-methyl-4- 2-hydroxylethyl 479 quinolinylmethoxy)benzoyl 2054-(2-methyl-4- 2-aminoethyl 478 quinolinylmethoxy)benzoyl 2064-(2-methyl-4- Cyclobutyl 489 quinolinylmethoxy)benzoyl 2074-(2-methyl-4- — 436 quinolinylmethoxy)benzoyl 208 4-(2-methyl-4-tert-butyl 491 quinolinylmethoxy)benzoyl 209 4-(2-methyl-4-tert-butyloxy-2- 577 quinolinylmethoxy)benzoyl methylpropanoate 2104-(2-methyl-4- 2-methylpropanoic 521 quinolinylmethoxy)benzoyl acid 2114-(2-methyl-4- methyl-2- 535 quinolinylmethoxy)benzoyl methylpropanoate212 4-(2-methyl-4- 2-(4-morpholinyl)- 562 quinolinylmethoxy)benzoyl2-oxoethyl 213 4-(2-methyl-4- 2-(dimethylamino)- 520quinolinylmethoxy)benzoyl 2-oxo 214 4-(2-methyl-4- 1,1-dimethyl-2- 503quinolinylmethoxy)benzoyl propenyl 215 4-(2-methyl-4- tert-pentyl 505quinolinylmethoxy)benzoyl 216 4-(2-methyl-4- 2-propynyl 473quinolinylmethoxy)benzoyl 217 4-(2-methyl-4- 2-propenyl 475quinolinylmethoxy)benzoyl 218 4-(2-methyl-4- 1-methyl-2- 487quinolinylmethoxy)benzoyl propynyl 219 4-(2-methyl-4- 1-methyl-2- 489quinolinylmethoxy)benzoyl propenyl 220 4-(2-methyl-4- — 466quinolinylmethoxy)benzoyl 221 4-(2-methyl-4- — 449quinolinylmethoxy)benzoyl 222 4-(2-methyl-4- — 449quinolinylmethoxy)benzoyl 223 4-(2-butynyloxy)benzoyl isopropyl 374 2244-(2-butynyloxy)benzoyl H 332 225 4-[(2-methyl-3- (1,1-dimethyl- 485pyridinyl)methoxy]benzoyl ethoxy)carbonyl 226 4-[(2-methyl-3- H 385pyridinyl)methoxy]benzoyl 227 4-(2,5- (1,1-dimethyl- 496dimethylbenzyl)oxy]benzoyl ethoxy)carbonyl 228 4-(2,5- H 398dimethylbenzyl)oxy]benzoyl} 301 4-(2-methyl-4- NH₂ 449quinolinylmethoxy)benzoyl 302 4-(2-methyl-4- NHMe 463quinolinylmethoxy)benzoyl 303 4-(2-methyl-4- NMe₂ 477quinolinylmethoxy)benzoyl 304 4-(2-methyl-4- NH₂ 449quinolinylmethoxy)benzoyl 305 4-(2-methyl-4- NMe₂ 477quinolinylmethoxy)benzoyl 306 4-(2-methyl-4- NH-i-Pr 491quinolinylmethoxy)benzoyl 307 4-(2-methyl-4- NHMe 463quinolinylmethoxy)benzoyl 308 4-(2-methyl-4- OH 450quinolinylmethoxy)benzoyl 309 4-{[(2-methyl-4- — 419quinolinyl)methyl]amino} benzoyl 310 4-{methyl[(2-methyl-4- — 433quinolinyl)methyl]amino} benzoyl 311 4-(3-phenyl-4,5-dihydro-5- — 394isoxazolyl)benzoyl 312 4-[3-(4-pyridinyl)-4,5- — 395dihydro-5-isoxazolyl]benzoyl 313 }-4-[3-(3-pyridinyl)-4,5- — 395dihydro-5-isoxazolyl]benzoyl 314 4-[3-(2-pyridinyl)-4,5- — 395dihydro-5-isoxazolyl]benzoyl 315 4-[3-(4-quinolinyl)-4,5- — 445dihydro-5-isoxazolyl]benzoyl 316 4-[3-(2,6-Dimethyl-4- — 423pyridinyl)-4,5-dihydro-5- isoxazolyl]benzoyl 317 3-methoxy-4-[3-(4- —425 pyridinyl)-4,5-dihydro-5- isoxazolyl]benzoyl 3184-[3-(4-pyridinyl)-4,5- — 411 dihydro-5-isoxazolyl]benzoyl 3194-[5-(2-pyridinyl)-4,5- — 395 dihydro-3-isoxazolyl]benzoyl 3204-[5-(4-pyridinyl)-4,5- — 395 dihydro-3-isoxazolyl]benzoyl 5011-[(2-methyl-4- H 444 quinolinyl)methyl]-1H- indole-5-carbonyl 5021-[(2-methyl-4- — 443 quinolinyl)methyl]-1H- indole-5-carbonyl 5036-[(2-methyl-4- H 485 quinolinyl)methoxy]-1- naphthoyl 5046-[(2-methyl-4- — 470 quinolinyl)methoxy]-1- naphthoyl 5056-[(2-methyl-4- — 470 quinolinyl)methoxy]-2- naphthoyl 5066-[(2-methyl-4- — 475 quinolinyl)methoxy]-1,2,3,4- tetrahydro-1-isoquinolinecarbonyl 507 1-[(2-methyl-4- — 444 quinolinyl)methyl]-1H-benzimidazole-5-carbonyl 508 1-[(2-methyl-4- — 443quinolinyl)methyl]-1H- indole-4-carboxamide 701 4-(2-methyl-4- — 448quinolinylmethoxy)benzoyl 702 4-(2-methyl-4- — 463quinolinylmethoxy)benzoyl 703 4-(2-methyl-4- — 463quinolinylmethoxy)benzoyl 704 4-(2-methyl-4- — 463quinolinylmethoxy)benzoyl 705 4-(2-methyl-4- H 421quinolinylmethoxy)benzoyl 706 4-(2-methyl-4- H 421quinolinylmethoxy)benzoyl 707 4-(2-methyl-4- (1,1-dimethyl- 521quinolinylmethoxy)benzoyl ethoxy)carbonyl

The following tables contain representative examples of the presentinvention. Each entry in each table is intended to be paired with eachformula at the start of the table. For example, example 1 is intended tobe paired with each of formulae A-AG.

TABLE 2

Ex # R¹⁰ 1 H 2 methyl 3 methoxy 4 1-methylethyl 5 1-methylethoxy 6phenyl 7 [1,1′-biphenyl]-4-yl 8 phenoxy 9 2-phenylethyl 102-(3,5-dimethylphenyl)ethyl 11 1-(2,6-dimethylphenyl)ethyl 122-phenylethenyl 13 phenoxymethyl 14 (2-methylphenyl)methoxy 15(3-methylphenyl)methoxy 16 3-methylphenoxy 17 2,6-dimethylphenoxy 18(2,6-dimethylphenyl)methoxy 19 3,5-dimethylphenoxy 20(3,5-dimethylphenyl)methoxy 21 2-(3,5-dimethylphenyl)ethyl 222-(3,5-dimethylphenyl)ethenyl 23 (3-amino-5-methylphenyl)methoxy 24(2-amino-6-methylphenyl)methoxy 25 (3-cyano-5-methylphenyl)methoxy 26(3-cyano-5-methylphenoxy)methyl 27 (3-cyano-5-nitrophenyl)methoxy 28(3,5-diethoxyphenyl)methoxy 29 (3,5-dimethoxyphenyl)methoxy 303,5-dimethoxyphenoxy 31 2-(3,5-dimethoxyphenyl)ethyl 321-(3,5-dimethoxyphenyl)ethoxy 33 (3,5-dichlorophenyl)methoxy 34(2,6-dichlorophenyl)methoxy 35 (3,5-dibromophenyl)methoxy 363,5-dibromophenoxy 37 (3-amino-5-cyanophenyl)methoxy 38[2,6-bis(trifluoromethyl)phenyl]methoxy 392,6-bis(trifluoromethyl)phenoxy 40(3-aminocarbonyl-5-methylphenyl)methoxy 41 ([1,1′-biphenyl]-2-yl)methoxy42 ([1,1′-biphenyl]-3-yl)methoxy 43[5-methyl-3-(methylsulfonyl)phenyl]methoxy 445-methyl-3-(methylsulfonyl)phenoxy 45 (2-pyridinyl)methoxy 46(4-pyridinyl)methoxy 47 (2,6-dimethyl-4-pyridinyl)methoxy 482,6-dimethyl-4-pyridinyloxy 49 1-(2,6-dimethyl-4-pyridinyl)ethoxy 50(3,5-dimethyl-4-pyridinyl)methoxy 51 (2,6-diethyl-4-pyridinyl)methoxy 52(2,6-dichloro-4-pyridinyl)methoxy 53 (2,6-dimethoxy-4-pyridinyl)methoxy54 (2-chloro-6-methyl-4-pyridinyl)methoxy 55(2-chloro-6-methoxy-4-pyridinyl)methoxy 56(2-methoxy-6-methyl-4-pyridinyl)methoxy 57 (1-naphthalenyl)methoxy 581-naphthalenyloxy 59 (2-naphthalenyl)methoxy 60(2-methyl-1-naphthalenyl)methoxy 61 (4-methyl-2-naphthalenyl)methoxy 62(4-quinolinyl)methoxy 63 1-(4-quinolinyl)ethoxy 64 4-quinolinyloxy 65(4-quinolinyloxy)methyl 66 2-(4-quinolinyl)ethyl 67(2-methyl-4-quinolinyl)methoxy 68 2-methyl-4-quinolinyloxy 69(2-chloro-4-quinolinyl)methoxy 70 (2-methoxy-4-quinolinyl)methoxy 71(2-hydroxy-4-quinolinyl)methoxy 72(2-trifluoromethyl-4-quinolinyl)methoxy 73(2-phenyl-4-quinolinyl)methoxy 74 (2,6-dimethyl-4-quinolinyl)methoxy 75(2,7-dimethyl-4-quinolinyl)methoxy 76 (5-quinolinyl)methoxy 77(7-methyl-5-quinolinyl)methoxy 78 (7-methoxy-5-quinolinyl)methoxy 79(8-quinolinyl)methoxy 80 2-(1,2,3-benzotriazol-1-yl)ethyl 81(2-benzimidazolyl)methoxy 82 (1,4-dimethyl-5-imidazolyl)methoxy 83(3,5-dimethyl-4-isoxazolyl)methoxy 84 (4,5-dimethyl-2-oxazolyl)methoxy85 (2,5-dimethyl-4-thiazolyl)methoxy 86 (3,5-dimethyl-1-pyrazolyl)ethyl87 (1,3-benzodioxo-4-yl)methoxy 88 (1,3,5-trimethyl-4-pyrazolyl)methoxy89 (2,6-dimethyl-4-pyrimidinyl)methoxy 90(4,5-dimethyl-2-furanyl)methoxy 91 (4,5-dimethyl-2-thiazolyl)methoxy 922-(2-oxazolyl)ethyl 93 2-butynyloxy 94 4-hydroxy-2-butynyloxy 954-pyridyl 96 4-pyridoxy 97 (2-methyl-4-quinolinyl)methylamino 983-phenyl-4,5-dihydro-5-isoxazolyl 993-(4-pyridinyl)-4,5-dihydro-5-isoxazolyl 1005-(4-pyridinyl)-4,5-dihydro-3-isoxazolyl

TABLE 3

Ex # R² 1 H 2 methyl 3 ethyl 4 1-methylethyl 5 cyclobutyl 6 n-butyl 72,2-dimethylpropyl 8 cyclopropylmethyl 9 2-methoxyethyl 102-hydroxyethyl 11 2-aminoethyl 12 2-dimethylaminoethyl 132-(4-morpholinyl)ethyl 14 2-(1-piperidinyl)ethyl 152-(1-piperizinyl)ethyl 16 phenyl 17 benzyl 18 3-picolyl 19 formyl 20acetyl 21 pivaloyl 22 benzoyl 23 nicotinoyl 24 methanesulfonyl 25benzenesulfonyl 26 t-butylsulfonyl 27 methoxycarbonyl 28t-butoxycarbonyl 29 isopropyloxycarbonyl 30 Dimethylcarbamyl 314-morpholinecarbonyl 32 2-thiophenecarbonyl 33 2-fluoroethyl 342,2-difluoroethyl 35 2-(dimethylamino)-2-oxoethyl 362-oxo-2-(4-morphorlinyl)ethyl 37 tert-butyl 38 1,1-dimethylpropyl 392-propenyl 40 1-methyl-2-propenyl 41 1,1-dimethyl-2-propenyl 422-propynyl 43 1-methyl-2-propynyl 44 1,1-dimethyl-2-propynyl 45(2-pyrrolidinyl)methyl

Utility

The compounds of formula I are expected to possess matrixmetalloprotease and/or aggrecanase and/or TNF-α inhibitory activity. TheMMP inhibitory activity of the compounds of the present invention isdemonstrated using assays of MMP activity, for example, using the assaydescribed below for assaying inhibitors of MMP activity. The compoundsof the present invention are expected to be bioavailable in vivo asdemonstrated, for example, using the ex vivo assay described below. Thecompounds of formula I are expected to have the ability tosuppress/inhibit cartilage degradation in vivo, for example, asdemonstrated using the animal model of acute cartilage degradationdescribed below.

The compounds provided by this invention should also be useful asstandards and reagents in determining the ability of a potentialpharmaceutical to inhibit MPs. These would be provided in commercialkits comprising a compound of this invention.

Metalloproteases have also been implicated in the degradation ofbasement membranes to allow infiltration of cancer cells into thecirculation and subsequent penetration into other tissues leading totumor metastasis (Stetler-Stevenson, Cancer and Metastasis Reviews, 9,289-303, 1990). The compounds of the present invention should be usefulfor the prevention and treatment of invasive tumors by inhibition ofthis aspect of metastasis.

The compounds of the present invention should also have utility for theprevention and treatment of osteopenia associated with matrixmetalloprotease-mediated breakdown of cartilage and bone that occurs inosteoporosis patients.

Compounds that inhibit the production or action of TNF and/orAggrecanase and/or MMP's are potentially useful for the treatment orprophylaxis of various inflammatory, infectious, immunological ormalignant diseases or conditions. Thus, the present invention relates toa method of treating various inflammatory, infectious, immunological ormalignant diseases. These include acute infection, acute phase response,age related macular degeneration, alcoholism, anorexia, asthma,autoimmune disease, autoimmune hepatitis, Bechet's disease, cachexia(including cachexia resulting from cancer or HIV), calcium pyrophosphatedihydrate deposition disease, cardiovascular effects, chronic fatiguesyndrome, chronic obstruction pulmonary disease, coagulation, congestiveheart failure, corneal ulceration, Crohn's disease, enteropathicarthropathy (including inflammatory bowl disease), Felty's syndrome,fever, fibromyalgia syndrome, fibrotic disease, gingivitis,glucocorticoid withdrawal syndrome, gout, graft versus host disease,hemorrhage, HIV infection, hyperoxic alveolar injury, infectiousarthritis, inflammation, intermittent hydrarthrosis, Lyme disease,meningitis, multiple sclerosis, myasthenia gravis, mycobacterialinfection, neovascular glaucoma, osteoarthritis, pelvic inflammatorydisease, periodontitis, polymyositis/dermatomyositis, post-ischaemicreperfusion injury, post-radiation asthenia, psoriasis, psoriaticarthritis, pydoderma gangrenosum, relapsing polychondritis, Reiter'ssyndrome, rheumatic fever, rheumatoid arthritis (including juvenilerheumatoid arthritis and adult rheumatoid arthritis), sarcoidosis,scleroderma, sepsis syndrome, Still's disease, shock, Sjogren'ssyndrome, skin inflammatory diseases, solid tumor growth and tumorinvasion by secondary metastases, spondylitis, stroke, systemic lupuserythematosus, ulcerative colitis, uveitis, vasculitis, and Wegener'sgranulomatosis.

Some compounds of the present invention have been shown to inhibit TNFproduction in lipopolysacharride stimulated mice, for example, using theassay for TNF induction in mice and in human whole blood as describedbelow.

Some compounds of the present invention have been shown to inhibitaggrecanase, a key enzyme in cartilage breakdown, as determined by theaggrecanase assay described below.

As used herein “ug” denotes microgram, “mg” denotes milligram, “g”denotes gram, “μL” denotes microliter, “mL” denotes milliliter, “L”denotes liter, “nM” denotes nanomolar, “pM” denotes micromolar, “mM”denotes millimolar, “M” denotes molar and “nm” denotes nanometer. “Sigmastands for the Sigma-Aldrich Corp. of St. Louis, Mo.

A compound is considered to be active if it has an IC₅₀ or K_(i) valueof less than about 10 μM for the inhibition of a desired MP. Preferredcompounds of the present invention have K_(i)'s or IC₅₀'s of ≦1 μM. Morepreferred compounds of the present invention have K_(i)'s or IC₅₀'s of≦0.1 μM. Even more preferred compounds of the present invention haveK_(i)'s or IC₅₀'s of ≦0.01 pM. Still more preferred compounds of thepresent invention have K_(i)'s or IC₅₀'s of ≦0.001 μM.

Aggrecanase Enzymatic Assay

A novel enzymatic assay was developed to detect potential inhibitors ofaggrecanase. The assay uses active aggrecanase accumulated in media fromstimulated bovine nasal cartilage (BNC) or related cartilage sources andpurified cartilage aggrecan monomer or a fragment thereof as asubstrate.

The substrate concentration, amount of aggrecanases time of incubationand amount of product loaded for Western analysis were optimized for useof this assay in screening putative aggrecanase inhibitors. Aggrecanaseis generated by stimulation of cartilage slices with interleukin-1(IL-1), tumor necrosis factor alpha (TNF-α) or other stimuli. Matrixmetalloproteases (MMPs) are secreted from cartilage in an inactive,zymogen form following stimulation, although active enzymes are presentwithin the matrix. We have shown that following depletion of theextracellular aggrecan matrix, active MMPs are released into the culturemedia (Tortorella, M. D. et. al. Trans. Ortho. Res. Soc. 20, 341, 1995).Therefore, in order to accumulate BNC aggrecanase in culture media,cartilage is first depleted of endogenous aggrecan by stimulation with500 ng/ml human recombinant IL-β for 6 days with media changes every 2days. Cartilage is then stimulated for an additional 8 days withoutmedia change to allow accumulation of soluble, active aggrecanase in theculture media. In order to decrease the amount of other matrixmetalloproteases released into the media during aggrecanaseaccumulation, agents which inhibit MMP-1, -2, -3, and -9 biosynthesisare included during stimulation. This BNC conditioned media, containingaggrecanase activity is then used as the source of aggrecanase for theassay. Aggrecanase enzymatic activity is detected by monitoringproduction of aggrecan fragments produced exclusively by cleavage at theGlu373-Ala374 bond within the aggrecan core protein by Western analysisusing the monoclonal antibody, BC-3 (Hughes, C E, et al., Biochem J306:799-804, 1995). This antibody recognizes aggrecan fragments with theN-terminus, 374ARGSVIL, generated upon cleavage by aggrecanase. The BC-3antibody recognizes this neoepitope only when it is at the N-terminusand not when it is present internally within aggrecan fragments orwithin the aggrecan protein core. Other proteases produced by cartilagein response to IL-1 do not cleave aggrecan at the Glu373-Ala374aggrecanase site; therefore, only products produced upon cleavage byaggrecanase are detected. Kinetic studies using this assay yield a Km of1.5+/−0.35 uM for aggrecanase.

To evaluate inhibition of aggrecanase, compounds are prepared as 10 mMstocks in DMSO, water or other solvents and diluted to appropriateconcentrations in water. Drug (50 ul) is added to 50 ul ofaggrecanase-containing media and 50 ul of 2 mg/ml aggrecan substrate andbrought to a final volume of 200 ul in 0.2 M Tris, pH 7.6, containing0.4 M NaCl and 40 mM CaCl₂. The assay is run for 4 hr at 37° C.,quenched with 20 mM EDTA and analyzed for aggrecanase-generatedproducts. A sample containing enzyme and substrate without drug isincluded as a positive control and enzyme incubated in the absence ofsubstrate serves as a measure of background.

Removal of the glycosaminoglycan side chains from aggrecan is necessaryfor the BC-3 antibody to recognize the ARGSVIL epitope on the coreprotein. Therefore, for analysis of aggrecan fragments generated bycleavage at the Glu373-Ala374 site, proteoglycans and proteoglycanfragments are enzymatically deglycosylated with chondroitinase ABC (0.1units/10 ug GAG) for 2 hr at 37° C. and then with keratanase (0.1units/10 ug GAG) and keratanase II (0.002 units/10 ug GAG) for 2 hr at37° C. in buffer containing 50 mM sodium acetate, 0.1 M Tris/HCl, pH6.5. After digestion, aggrecan in the samples is precipitated with 5volumes of acetone and resuspended in 30 ul of Tris glycine SDS samplebuffer (Novex) containing 2.5% beta mercaptoethanol. Samples are loadedand then separated by SDS-PAGE under reducing conditions with 4-12%gradient gels, transferred to nitrocellulose and immunolocated with1:500 dilution of antibody BC3. Subsequently, membranes are incubatedwith a 1:5000 dilution of goat anti-mouse IgG alkaline phosphatasesecond antibody and aggrecan catabolites visualized by incubation withappropriate substrate for 10-30 minutes to achieve optimal colordevelopment. Blots are quantitated by scanning densitometry andinhibition of aggrecanase determined by comparing the amount of productproduced in the presence versus absence of compound.

TNF PBMC Assay

Human peripheral blood mononuclear cells (PBMC) were obtained fromnormal donor blood by leukophoresis and isolated by Ficoll-Paque densityseparation. PBMCs were suspended in 0.5 ml RPMI 1640 with no serum at2×10⁶ cells/ml in 96 well polystyrene plates. Cells were preincubated 10minutes with compound, then stimulated with 1 ug/ml LPS(Lipopolysaccharide, Salmonella typhimurium) to induce TNF production.After an incubation of 5 hours at 37° C. in 95% air, 5% CO₂ environment,culture supernatants were removed and tested by standard sandwich ELISAfor TNF production.

TNF Human Whole Blood Assay

Blood is drawn from normal donors into tubes containing 143 USP units ofheparin/10 ml. 225 ul of blood is plated directly into sterilepolypropylene tubes. Compounds are diluted in DMSO/serum free media andadded to the blood samples so the final concentration of compounds are50, 10, 5, 1, 0.5, 0.1, and 0.01 μM. The final concentration of DMSOdoes not exceed 0.5%. Compounds are preincubated for 15 minutes beforethe addition of 100 ng/ml LPS. Plates are incubated for 5 hours in anatmosphere of 5% CO₂ in air. At the end of 5 hours, 750 ul of serum freemedia is added to each tube and the samples are spun at 120ORPM for 10minutes. The supernatant is collected off the top and assayed forTNF-alpha production by a standard sandwich ELISA. The ability ofcompounds to inhibit TNF-alpha production by 50% compared to DMSOtreated cultures is given by the IC50 value.

TNF Induction in Mice

Test compounds are administered to mice either I.P. or P.O. at timezero. Immediately following compound administration, mice receive anI.P. injection of 20 mg of D-galactosamine plus 10 μg oflipopolysaccharide. One hour later, animals are anesthetized and bled bycardiac puncture. Blood plasma is evaluated for TNF levels by an ELISAspecific for mouse TNF. Administration of representative compounds ofthe present invention to mice results in a dose-dependent suppression ofplasma TNF levels at one hour in the above assay.

MMP Assays

The enzymatic activities of recombinant MMP-1, 2, 3, 7, 8, 9, 13, 14,15, and 16 were measured at 25° C. with a fluorometric assay (Copeland,R. A.; Lombardo, D.; Giannaras, J. and Decicco, C. P. Bioorganic Med.Chem. Lett. 1995, 5, 1947-1952). Final enzyme concentrations in theassay were between 0.05 and 10 nM depending on the enzyme and thepotency of the inhibitor tested. The permisive peptide substrate,MCA-Pro-Leu-Gly-Leu-DPA-Ala-Arg-NH₂, was present at a finalconcentration of 10 uM in all assays. Initial velocities, in thepresence or absence of inhibitor, were measured as slopes of the linearportion of the product progress curves. IC50 values were determined byplotting the inhibitor concentration dependence of the fractionalvelocity for each enzyme, and fitting the data by non-linear leastsquares methods to the standard isotherm equation (Copeland, R. A.Enzymes: A practical Introduction to Structure, Mechanism and DataAnalysis, Wiley-VHC, New York, 1996, pp 187-223). All of the compoundsstudied here were assumed to act as competitive inhibitors of theenzyme, binding to the active site Zn atom as previously demonstrated bycrystallographic studies of MMP-3 complexed with related hydroxamicacids (Rockwell, A.; Melden, M.; Copeland, R. A.; Hardman, K.; Decicco,C. P. and DeGrado, W. F. J. Am. Chem. Soc. 1996, 118, 10337-10338).Based on the assumption of competitive inhibiton, the IC50 values wereconverted to Ki values as previously described.

Compounds tested in the above assay are considered to be active if theyexhibit a K_(i) of ≦10 μM. Preferred compounds of the present inventionhave K_(i)'s of ≦1 μM. More preferred compounds of the present inventionhave K_(i)'s of ≦0.1 μM. Even more preferred compounds of the presentinvention have K_(i)'s of ≦0.01 μM. Still more preferred compounds ofthe present invention have K_(i)'s of ≦0.001 μM.

Using the methodology described above, a number of compounds of thepresent invention were found to exhibit K_(i)'s of ≦10 μM, therebyconfirming the utility of the compounds of the present invention.

Dosage and Formulation

The compounds of the present invention can be administered orally usingany pharmaceutically acceptable dosage form known in the art for suchadministration. The active ingredient can be supplied in solid dosageforms such as dry powders, granules, tablets or capsules, or in liquiddosage forms, such as syrups or aqueous suspensions. The activeingredient can be administered alone, but is generally administered witha pharmaceutical carrier. A valuable treatise with respect topharmaceutical dosage forms is Remington's Pharmaceutical Sciences, MackPublishing.

The compounds of the present invention can be administered in such oraldosage forms as tablets, capsules (each of which includes sustainedrelease or timed release formulations), pills, powders, granules,elixirs, tinctures, suspensions, syrups, and emulsions. Likewise, theymay also be administered in intravenous (bolus or infusion),intraperitoneal, subcutaneous, or intramuscular form, all using dosageforms well known to those of ordinary skill in the pharmaceutical arts.An effective but non-toxic amount of the compound desired can beemployed as an antiinflammatory and antiarthritic agent.

The compounds of this invention can be administered by any means thatproduces contact of the active agent with the agent's site of action inthe body of a mammal. They can be administered by any conventional.means available for use in conjunction with pharmaceuticals, either asindividual therapeutic agents or in a combination of therapeutic agents.They can be administered alone, but generally administered with apharmaceutical carrier selected on the basis of the chosen route ofadministration and standard pharmaceutical practice.

The dosage regimen for the compounds of the present invention will, ofcourse, vary depending upon known factors, such as the pharmacodynamiccharacteristics of the particular agent and its mode and route ofadministration; the species, age, sex, health, medical condition, andweight of the recipient; the nature and extent of the symptoms; the kindof concurrent treatment; the frequency of treatment; the route ofadministration, the renal and hepatic function of the patient,and theeffect desired. An ordinarily skilled physician or veterinarian canreadily determine and prescribe the effective amount of the drugrequired to prevent, counter, or arrest the progress of the condition.

By way of general guidance, the daily oral dosage of each activeingredient, when used for the indicated effects, will range betweenabout 0.001 to 1000 mg/kg of body weight, preferably between about 0.01to 100 mg/kg of body weight per day, and most preferably between about1.0 to 20 mg/kg/day. For a normal male adult human of approximately 70kg of body weight, this translates into a dosage of 70 to 1400 mg/day.Intravenously, the most preferred doses will range from about 1 to about10 mg/kg/minute during a constant rate infusion. Advantageously,compounds of the present invention may be administered in a single dailydose, or the total daily dosage may be administered in divided doses oftwo, three, or four times daily.

The compounds for the present invention can be administered inintranasal form via topical use of suitable intranasal vehicles, or viatransdermal routes, using those forms of transdermal skin patches wallknown to those of ordinary skill in that art. To be administered in theform of a transdermal delivery system, the dosage administration will,of course, be continuous rather than intermittant throughout the dosageregimen.

In the methods of the present invention, the compounds herein describedin detail can form the active ingredient, and are typically administeredin admixture with suitable pharmaceutical diluents, excipients, orcarriers (collectively referred to herein as carrier materials) suitablyselected with respect to the intended form of administration, that is,oral tablets, capsules, elixirs, syrups and the like, and consistentwith conventional pharmaceutical practices.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic, pharmaceutically acceptable, inert carrier such as lactose,starch, sucrose, glucose, methyl callulose, magnesium stearate,dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like;for oral administration in liquid form, the oral drug components can becombined with any oral, non-toxic, pharmaceutically acceptable inertcarrier such as ethanol, glycerol, water, and the like. Moreover, whendesired or necessary, suitable binders, lubricants, disintegratingagents, and coloring agents can also be incorporated into the mixture.Suitable binders include starch, gelatin, natural sugars such as glucoseor beta-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth, or sodium alginate, carboxymethylcellulose,polyethylene glycol, waxes, and the like. Lubricants used in thesedosage forms include sodium oleate, sodium stearate, magnesium stearate,sodium benzoate, sodium acetate, sodium chloride, and the like.Disintegrators include, without limitation, starch, methyl cellulose,agar, bentonite, xanthan gum, and the like.

The compounds of the present invention can also be administered in theform of liposome delivery systems, such as small unilamellar vesicles,large unilamallar vesicles, and multilamellar vesicles. Liposomes can beformed from a variety of phospholipids, such as cholesterol,stearylamine, or phosphatidylcholines.

Compounds of the present invention may also be coupled with solublepolymers as targetable drug carriers. Such polymers can includepolyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamide-phenol,polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysinesubstituted with palmitoyl residues. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polyglycolic acid, copolymers of polylactic andpolyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, andcrosslinked or amphipathic block copolymers of hydrogels.

Dosage forms (pharmaceutical compositions) suitable for administrationmay contain from about 1 milligram to about 100 milligrams of activeingredient per dosage unit. In these pharmaceutical compositions theactive ingredient will ordinarily be present in an amount of about0.5-95% by weight based on the total weight of the composition.

The active ingredient can be administered orally in solid dosage forms,such as capsules, tablets, and powders, or in liquid dosage forms, suchas elixirs, syrups, and suspensions. It can also be administeredparenterally, in sterile liquid dosage forms.

Gelatin capsules may contain the active ingredient and powderedcarriers, such as lactose, starch, cellulose derivatives, magnesiumstearate, stearic acid, and the like. Similar diluents can be used tomake compressed tablets. Both tablets and capsules can be manufacturedas sustained release products to provide for continuous release ofmedication over a period of hours. Compressed tablets can be sugarcoated or film coated to mask any unpleasant taste and protect thetablet from the atmosphere, or enteric coated for selectivedisintegration in the gastrointestinal tract.

Liquid dosage forms for oral administration can contain coloring andflavoring to increase patient acceptance. In general, water, a suitableoil, saline, aqueous dextrose (glucose), and related sugar solutions andglycols such as propylene glycol or polyethylene glycols are suitablecarriers for parenteral solutions. Solutions for parenteraladministration preferably contain a water soluble salt of the activeingredient, suitable stabilizing agents, and if necessary, buffersubstances. Antioxidizing agents such as sodium bisulfite, sodiumsulfite, or ascorbic acid, either alone or combined, are suitablestabilizing agents. Also used are citric acid and its salts and sodiumEDTA. In addition, parenteral solutions can contain preservatives, suchas benzalkonium chloride, methyl-or propyl-paraben, and chlorobutanol.

Suitable pharmaceutical carriers are described in Remington'sPharmaceutical Sciences, Mack Publishing Company, a standard referencetext in this field. Useful pharmaceutical dosage-forms foradministration of the compounds of this invention can be illustrated asfollows:

Capsules

Capsules are prepared by conventional procedures so that the dosage unitis 500 milligrams of active ingredient, 100 milligrams of cellulose and10 milligrams of magnesium stearate.

A large number of unit capsules may also prepared by filling standardtwo-piece hard gelatin capsules each with 100 milligrams of powderedactive ingredient, 150 milligrams of lactose, 50 milligrams ofcellulose, and 6 milligrams magnesium stearate.

Syrup Wt. % Active Ingredient 10 Liquid Sugar 50 Sorbitol 20 Glycerine 5Flavor, Colorant and as required Preservative Water as required

The final volume is brought up to 100% by the addition of distilledwater.

Aqueous Suspension Wt. % Active Ingredient 10 Sodium Saccharin 0.01Keltrol ® (Food Grade Xanthan Gum) 0.2 Liquid Sugar 5 Flavor, Colorantand as required Preservative Water as required

Xanthan gum is slowly added into distilled water before adding theactive ingredient and the rest of the formulation ingredients. The finalsuspension is passed through a homogenizer to assure the elegance of thefinal products.

Resuspendable Powder Wt. % Active Ingredient 50.0 Lactose 35.0 Sugar10.0 Acacia 4.7 Sodium Carboxylmethylcellulose 0.3

Each ingredient is finely pulverized and then uniformly mixed together.Alternatively, the powder can be prepared as a suspension and then spraydried.

Semi-Solid Gel Wt. % Active Ingredient 10 Sodium Saccharin 0.02 Gelatin2 Flavor, Colorant and as required Preservative Water as required

Gelatin is prepared in hot water. The finely pulverized activeingredient is suspended in the gelatin solution and then the rest of theingredients are mixed in. The suspension is filled into a suitablepackaging container and cooled down to form the gel.

Semi-Solid Paste Wt. % Active Ingredient 10 Gelcarin ® (Carrageenin gum)1 Sodium Saccharin 0.01 Gelatin 2 Flavor, Colorant and as requiredPreservative Water as required

Gelcarin® is dissolved in hot water (around 80° C.) and then thefine-powder active ingredient is suspended in this solution. Sodiumsaccharin and the rest of the formulation ingredients are added to thesuspension while it is still warm. The suspension is homogenized andthen filled into suitable containers.

Emulsifiable Paste Wt. % Active Ingredient 30 Tween ® 80 and Span ® 80 6Keltrol ® 0.5 Mineral Oil 63.5

All the ingredients are carefully mixed together to make a homogenouspaste.

Soft Gelatin Capsules

A mixture of active ingredient in a digestable oil such as soybean oil,cottonseed oil or olive oil is prepared and injected by means of apositive displacement pump into gelatin to form soft gelatin capsulescontaining 100 milligrams of the active ingredient. The capsules arewashed and dried.

Tablets

Tablets may be prepared by conventional procedures so that the dosageunit is 500 milligrams of active ingredient, 150 milligrams of lactose,50 milligrams of cellulose and 10 milligrams of magnesium stearate.

A large number of tablets may also be prepared by conventionalprocedures so that the dosage unit was 100 milligrams of activeingredient, 0.2 milligrams of colloidal silicon dioxide, 5 milligrams ofmagnesium stearate, 275 milligrams of microcrystalline cellulose, 11milligrams of starch and 98.8 milligrams of lactose. Appropriatecoatings may be applied to increase palatability or delay absorption.

Injectable

A parenteral composition suitable for administration by injection isprepared by stirring 1.5% by weight of active ingredient in 10% byvolume propylene glycol and water. The solution is made isotonic withsodium chloride and sterilized.

Suspension

An aqueous suspension is prepared for oral administration so that each 5mL contain 100 mg of finely divided active ingredient, 200 mg of sodiumcarboxymethyl cellulose, 5 mg of sodium benzoate, 1.0 g of sorbitolsolution, U.S.P., and 0.025 mL of vanillin.

The compounds of the present invention may be administered incombination with a second therapeutic agent, especially non-steroidalanti-inflammatory drugs (NSAID's). The compound of Formula I and suchsecond therapeutic agent can be administered separately or as a physicalcombination in a single dosage unit, in any dosage form and by variousroutes of administration, as described above.

The compound of Formula I may be formulated together with the secondtherapeutic agent in a single dosage unit (that is, combined together inone capsule, tablet, powder, or liquid, etc.). When the compound ofFormula I and the second therapeutic agent are not formulated togetherin a single dosage unit, the compound of Formula I and the secondtherapeutic agent may be administered essentially at the same time, orin any order; for example the compound of Formula I may be administeredfirst, followed by administration of the second agent. When notadministered at the same time, preferably the administration of thecompound of Formula I and the second therapeutic agent occurs less thanabout one hour apart, more preferably less than about 5 to 30 minutesapart.

Preferably the route of administration of the compound of Formula I isoral. Although it is preferable that the compound of Formula I and thesecond therapeutic agent are both administered by the same route (thatis, for example, both orally), if desired, they may each be administeredby different routes and in different dosage forms (that is, for example,one component of the combination product may be administered orally, andanother component may be administered intravenously).

The dosage of the compound of Formula I when administered alone or incombination with a second therapeutic agent may vary depending uponvarious factors such as the pharmacodynamic characteristics of theparticular agent and its mode and route of administration, the age,health and weight of the recipient, the nature and extent of thesymptoms, the kind of concurrent treatment, the frequency of treatment,and the effect desired, as described above. Particularly when providedas a single dosage unit, the potential exists for a chemical interactionbetween the combined active ingredients. For this reason, when thecompound of Formula I and a second therapeutic agent are combined in asingle dosage unit they are formulated such that although the activeingredients are combined in a single dosage unit, the physical contactbetween the active ingredients is minimized (that is, reduced). Forexample, one active ingredient may be enteric coated. By enteric coatingone of the active ingredients, it is possible not only to minimize thecontact between the combined active ingredients, but also, it ispossible to control the release of one of these components in thegastrointestinal tract such that one of these components is not releasedin the stomach but rather is released in the intestines. One of theactive ingredients may also be coated with a sustained-release materialwhich effects a sustained-release throughout the gastrointestinal tractand also serves to minimize physical contact between the combined activeingredients. Furthermore, the sustained-released component can beadditionally enteric coated such that the release of this componentoccurs only in the intestine. Still another approach would involve theformulation of a combination product in which the one component iscoated with a sustained and/or enteric release polymer, and the othercomponent is also coated with a polymer such as a lowviscosity grade ofhydroxypropyl methylcellulose (HPMC) or other appropriate materials asknown in the art, in order to further separate the active components.The polymer coating serves to form an additional barrier to interactionwith the other component.

These as well as other ways of minimizing contact between the componentsof combination products of the present invention, whether administeredin a single dosage form or administered in separate forms but at thesame time by the same manner, will be readily apparent to those skilledin the art, once armed with the present disclosure.

The present invention also includes pharmaceutical kits useful, forexample, in the treatment or prevention of osteoarthritis or rheumatoidarthritis, which comprise one or more containers containing apharmaceutical composition comprising a therapeutically effective amountof a compound of Formula I. Such kits may further include, if desired,one or more of various conventional pharmaceutical kit components, suchas, for example, containers with one or more pharmaceutically acceptablecarriers, additional containers, etc., as will be readily apparent tothose skilled in the art. Instructions, either as inserts or as labels,indicating quantities of the components to be administered, guidelinesfor administration, and/or guidelines for mixing the components, mayalso be included in the kit.

In the present disclosure it should be understood that the specifiedmaterials and conditions are important in practicing the invention butthat unspecified materials and conditions are not excluded so long asthey do not prevent the benefits of the invention from being realized.

Although this invention has been described with respect to specificembodiments, the details of these embodiments are not to be construed aslimitations. Various equivalents, changes and modifications may be madewithout departing from the spirit and scope of this invention, and it isunderstood that such equivalent embodiments are part of this invention.

1. A compound of formula I:

or a stereoisomer or pharmaceutically acceptable salt form thereof,wherein; A is selected from —COR⁵, —CO₂H, CH₂CO₂H, —CO₂R⁶, —CONHOH,—CONHOR⁵, —CONHOR⁶, —N(OH)COR⁵, —N(OH)CHO, —SH, —CH₂SH, —S(O)(═NH)R^(a),—SN₂H₂R^(a), —PO(OH)₂, and —PO(OH)NHR^(a); ring B is piperidinyl orpyridinyl; Z is phenyl substituted with 0-4 R^(b), naphthyl substitutedwith 0-5 R^(b), or tetrahydronaphthyl substituted with 0-5 R^(b); U^(a)is absent or is selected from: O, NR^(a) ¹ , C(O), C(O)O, OC(O),C(O)NR^(a) ¹ , NR^(a) ¹ C(O), OC(O)O, OC(O)NR^(a) ¹ , NR^(a) ¹ C(O)O,NR^(a) ¹ C(O)NR^(a) ¹ , S(O)_(p), S(O)_(p)NR^(a) ¹ , NR^(a) ¹ S(O)_(p),and NR^(a) ¹ SO₂NR^(a) ¹ ; X^(a) is absent or selected from C₁₋₁₀alkylene, C₂₋₁₀ alkenylene, and C₂₋₁₀ alkynylene; Y^(a) is absent orselected from O, NR^(a) ¹ , S(O)_(p), and C(O); Z^(a) is pyridylsubstituted with 0-4 R^(c) or quinolinyl substituted with 0-5 R^(c); R¹is selected from H, C₁₋₄ alkyl, phenyl, and benzyl; R² is selected fromO, Cl, F, C₁₋₁₀ alkylene-Q substituted with 0-3 R^(b1), C₂₋₁₀alkenylene-Q substituted with 0-3 R^(b1), C₂₋₁₀ alkynylene-Q substitutedwith 0-3 R^(b1), (CR^(a)R^(a) ¹ )_(r) _(i) O(CR^(a)R^(a) ¹ )_(r)-Q,(CR^(a)R^(a) ¹ )_(r) ₁ NR^(a)(CR^(a)R^(a) ¹ )_(r)-Q, (CR^(a)R^(a) ¹)_(r) ₁ C(O)(CR^(a)R^(a) ¹ )_(r)-Q, (CR^(a)R^(a) ¹ )_(r) ₁C(O)O(CR^(a)R^(a) ¹ )_(r)-Q, (CR^(a)R^(a) ¹ )_(r) ₁ C(O)O—C₂₋₅alkenylene, (CR^(a)R^(a) ¹ )_(r) ₁ C(O)O—C₂₋₅ alkynylene, (CR^(a)R^(a) ¹)_(r) ₁ OC(O)(CR^(a)R^(a) ¹ )_(R)-Q, (CR^(a)R^(a) ¹ )_(r) ₁C(O)NR^(a)(CR^(a)R^(a) ¹ )_(r)-Q, (CR^(a)R^(a) ¹ )_(r) ₁NR^(a)C(O)(CR^(a)R^(a) ¹ )_(r)-Q, (CR^(a)R^(a) ¹ )_(r) ₁OC(O)O(CR^(a)R^(a) ¹ )_(r)-Q, (CR^(a)R^(a) ¹ )_(r) ₁OC(O)NR^(a)(CR^(a)R^(a) ¹ )_(r)-Q, (CR^(a)R^(a) ¹ )_(r) ₁NR^(a)C(O)O(CR^(a)R^(a) ¹ )_(r)-Q, (CR^(a)R^(a) ¹ )_(r) ₁NR^(a)C(O)NR^(a)(CR^(a)R^(a) ¹ )_(r)-Q, (CR^(a)R^(a) ¹ )_(r) ₁S(O)_(p)(CR^(a)R^(a) ¹ )_(r)-Q, (CR^(a)R^(a) ¹ )_(r) ₁SO₂NR^(a)(CR^(a)R^(a) ¹ )_(r)-Q, (CR^(a)R^(a) ¹ )_(r) ₁NR^(a)SO₂(CR^(a)R^(a) ¹ )_(r)-Q, and (CR^(a)R^(a) ¹ )_(r) ₁NR^(a)SO₂NR^(a)(CR^(a)R^(a) ¹ )^(r)-Q; R^(2a) is selected from H, C₁₋₆alkyl, OR^(a), NR^(a)R^(a) ¹ , and S(O)_(p)R^(a); R^(2b) is H or C₁₋₆alkyl; Q is selected from H, and a C₃₋₁₃ carbocycle substituted with 0-5R^(d) R³ is selected from Q¹, Cl, F, C₁₋₆ alkylene-Q¹, C₂₋₆alkenylene-Q¹, C₂₋₆ alkynylene-Q¹, (CR^(a)R^(a) ¹ )_(r) ₁ O(CR^(a)R^(a)¹ )_(r)-Q¹, (CR^(a)R^(a) ¹ )_(r) ₁ NR^(a)(CR^(a)R^(a) ¹ )_(r)-Q¹,(CR^(a)R^(a) ¹ )_(r) ₁ NR^(a)C(O)(CR^(a)R^(a) ¹ )_(r)-Q¹, (CR^(a)R^(a) ¹)_(r) ₁ C(O)NR^(a)(CR^(a)R^(a) ¹ )_(r)-Q¹, (CR^(a)R^(a) ¹ )_(r) ₁C(O)(CR^(a)R^(a) ¹ )_(r)-Q¹, (CR^(a)R^(a) ¹ )_(r) ₁ C(O)O(CR^(a)R^(a) ¹)_(r)-Q¹, (CR^(a)R^(a) ¹ ₂)_(r) ₁ S(O)_(p)(CR^(a)R^(a) ¹ )_(r)-Q¹, and(CR^(a)R^(a) ¹ )_(r) ₁ SO₂NR^(a)(CR^(a)R^(a) ¹ )_(r)-Q¹; Q¹ is selectedfrom H, phenyl substituted with 0-3 R^(d), and naphthyl substituted with0-3 R^(d) R^(a), at each occurrence, is independently selected from H,C₁₋₄ alkyl, phenyl and benzyl; R^(a) ¹ , each occurrence, isindependently selected from H and C₁₋₄ alkyl, alternatively, R^(a) andR^(a) ¹ when attached to a nitrogen are taken together with the nitrogento which they are attached to form a 5 or 6 membered ring comprisingcarbon atoms and from 0-1 additional heteroatoms selected from the groupconsisting of N, O, and S(O)_(p); R^(a) ² , at each occurrence, isindependently selected from C₁₋₄ alkyl, phenyl and benzyl; R^(b), ateach occurrence, is independently selected from C₁₋₆ alkyl, OR^(a), Cl,F, Br, I, ═O, —CN, NO₂, NR^(a)R^(a), C(O)R^(a), C(O)OR^(a),C(O)NR^(a)R^(a) ¹ , R^(a)NC(O)NR^(a)R^(a) ¹ , OC(O)NR^(a)R^(a) ¹ ,R^(a)NC(O)O, S(O)₂NR^(a)R^(a) ¹ , NR^(a)S(O)₂R^(a) ² ,NR^(a)S(O)₂NR^(a)R^(a) ¹ , OS(O)₂NR^(a)R^(a) ¹ , NR^(a)S(O)₂R^(a) ² ,S(O)_(p)R^(a) ² , CF₃, and CF₂CF₃; R^(b) ¹ , at each occurrence, isindependently selected from OR^(a), Cl, F, Br, I, ═O, —CN, NO₂, andNR^(a)R^(a) ¹ ; R^(c), at each occurrence, is independently selectedfrom C₁₋₆ alkyl, OR^(a), Cl, F, Br, I, ═O, —CN, NO₂, NR^(a)R^(a),C(O)R^(a), C(O)OR^(a), C(O)NR^(a)R^(a) ¹ , R^(a)NC(O)NR^(a)R^(a) ¹ ,OC(O)NR^(a)R^(a) ¹ , R^(a)NC(O)O, S(O)₂NR^(a)R^(a) ¹ , NR^(a)S(O)₂R^(a)² , NR^(a)S(O)₂NR^(a)R^(a) ¹ , OS(O)₂NR^(a)R^(a) ¹ , NR^(a)S(O)₂R^(a) ², S(O)_(p)R^(a) ² , CF₃, CF₂CF₃, and C₃₋₁₀ carbocycle substituted with0-3 R^(c1); R^(c1), at each occurrence, is independently selected fromC₁₋₆ alkyl, OR^(a), Cl, F, Br, I, ═O, —CN, NO₂, NR^(a)R^(a), C(O)R^(a),C(O)OR^(a), C(O)NR^(a)R^(a) ¹ , R^(a)NC(O)NR^(a)R^(a) ¹ ,OC(O)NR^(a)R^(a) ¹ , R^(a)NC(O)O, S(O)₂NR^(a)R^(a) ¹ , NR^(a)S(O)₂R^(a)² , NR^(a)S(O)₂NR^(a)R^(a) ¹ , OS(O)₂NR^(a)R^(a) ¹ , NR^(a)S(O)₂R^(a) ², S(O)_(p)R^(a) ² , CF₃, and CF₂CF₃; R^(d), at each occurrence, isindependently selected from C₁₋₆ alkyl, OR^(a), Cl, F, Br, I, ═O, —CN,NO₂, NR^(a)R^(a), C(O)R^(a), C(O)OR^(a), C(O)NR^(a)R^(a) ¹ ,R^(a)NC(O)NR^(a)R^(a) ¹ , OC(O)NR^(a)R^(a) ¹ , R^(a)NC(O)O,S(O)₂NR^(a)R^(a) ¹ , NR^(a)S(O)₂R^(a) ² , NR^(a)S(O)₂NR^(a)R^(a) ¹ ,OS(O)₂NR^(a)R^(a) ¹ , NR^(a)S(O)₂R^(a) ² , S(O)_(p)R^(a) ² , CF₃,CF₂CF₃, and C₃₋₁₀ carbocycle; R⁵, at each occurrence, is selected fromC₁₋₁₀ alkyl substituted with 0-2 R^(b), and C₁₋₈ alkyl substituted with0-2 R^(e); R^(e), at each occurrence, is selected from phenylsubstituted with 0-2 R^(b) and biphenyl substituted with 0-2 R^(b); R⁶,at each occurrence, is selected from phenyl, naphthyl, C₁₋₁₀alkyl-phenyl-C₁₋₆ alkyl-, C₃₋₁₁ cycloalkyl, C₁₋₆ alkylcarbonyloxy-C₁₋₃alkyl-, C₁₋₆ alkoxycarbonyloxy-C₁₋₃ alkyl-, C₂₋₁₀ alkoxycarbonyl, C₃₋₆cycloalkylcarbonyloxy-C₁₋₃ alkyl-, C₃₋₆ cycloalkoxycarbonyloxy-C₁₋₃alkyl-, C₃₋₆ cycloalkoxycarbonyl, phenoxycarbonyl,phenyloxycarbonyloxy-C₁₋₃ alkyl-, phenylcarbonyloxy-C₁₋₃ alkyl-, C₁₋₆alkoxy-C₁₋₆ alkylcarbonyloxy-C₁₋₃ alkyl-, [5-(C₁-C₅alkyl)-1,3-dioxa-cyclopenten-2-one-yl]methyl,[5-(R^(a))-1,3-dioxa-cyclopenten-2-one-yl]methyl,(5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyl, —C₁₋₁₀ alkyl-NR⁷R^(7a),—CH(R⁸)OC(═O)R⁹, and —CH(R⁸)OC(═O)OR⁹; R⁷ is selected from H and C₁₋₁₀alkyl, C₂₋₆ alkenyl, C₃₋₆ cycloalkyl-C₁₋₃ alkyl-, and phenyl-C₁₋₆alkyl-; R^(7a) is selected from H and C₁₋₁₀ alkyl, C₂₋₆ alkenyl, C₃₋₆cycloalkyl-C₁₋₃ alkyl-, and phenyl-C₁₋₆ alkyl-; R⁸ is selected from Hand C₁₋₄ linear alkyl; R⁹ is selected from H, C₁₋₈ alkyl substitutedwith 1-2 R^(f), C₃₋₈ cycloalkyl substituted with 1-2 R^(f), and phenylsubstituted with 0-2 R^(b); R^(f), at each occurrence, is selected fromC₁₋₄ alkyl, C₃₋₈ cycloalkyl, C₁₋₅ alkoxy, and phenyl substituted with0-2 R^(b); p, at each occurrence, is selected from 0, 1, and 2; r, ateach occurrence, is selected from 0, 1, 2, 3, and 4; and, r¹, at eachoccurrence, is selected from 0, 1, 2, 3, and
 4. 2. A compound accordingto claim 1, wherein the compound is of formula II:

or a stereoisomer or pharmaceutically acceptable salt form thereof,wherein; A is selected from —CO₂H. CH₂CO₂H, —CONHOH, —CONHOR⁵, —CONHOR⁶,—N(OH)COR⁵, —N(OH)CHO, —SH, and —CH₂SH; ring B is piperidinyl orpyridinyl; Z is phenyl substituted with 0-4 R^(b), naphthyl substitutedwith 0-4 R^(b), or tetrahydronaphthyl substituted with 0-4 R^(b); U^(a)is absent or is selected from: O, NR^(a) ¹ , C(O), C(O)O, C(O)NR^(a) ¹ ,NR^(a) ¹ C(O), S(O)_(p), and S(O)_(p)NR^(a) ¹ ; X^(a) is absent orselected from C₁₋₄ alkylene, C₂₋₄ alkenylene, and C₂₋₄ alkynylene; Y^(a)is absent or selected from O and NR^(a) ¹ ; Z^(a) is pyridyl substitutedwith 0-4 R^(c) or quinolinyl substituted with 0-5 R^(c); provided thatZ, U^(a), Y^(a), and Z^(a) do not combine to form a N—N, N—O, O—N, O—O,S(O)_(p)—O, O—S(O)_(p) or S(O)_(p)—S(O)_(p) group; R¹ is selected fromH, C₁₋₄ alkyl, phenyl, and benzyl; R² is selected from O, C₁₋₆alkylene-Q, C₂₋₆ alkenylene-Q, C₂₋₆ alkynylene-Q, (CR^(a)R^(a) ¹ )_(r) ₁O(CR^(a)R^(a) ¹ )_(r)-Q, (CR^(a)R^(a) ¹ )_(r) ₁ NR^(a)(CR^(a)R^(a) ¹)_(r)-Q, (CR^(a)R^(a) ¹ )_(r) ₁ C(O)(CR^(a)R^(a) ¹ )_(r)-Q, (CR^(a)R^(a)¹ )_(r) ₁ C(O)O(CR^(a)R^(a) ¹ )_(r)-Q, (CR^(a)R^(a) ¹)_(r)C(O)NR^(a)R^(a) ¹ , (CR^(a)R^(a) ¹ )_(r) ₁ C(O)NR^(a)(CR^(a)R^(a) ¹)_(r)-Q, (CR^(a)R^(a) ¹ )_(r) ₁ S(O)_(p)(CR^(a)R^(a) ¹ )_(r)-Q, and(CR^(a)R^(a) ¹ )_(r) ₁ SO₂NR^(a)(CR^(a)R^(a) ¹ )_(r)-Q; Q is selectedfrom H, and a C₃₋₆ carbocycle substituted with 0-5 R^(d); R^(a), at eachoccurrence, is independently selected from H, C₁₋₄ alkyl, phenyl andbenzyl; R^(a) ¹ , at each occurrence, is independently selected from Hand C₁₋₄ alkyl; alternatively, R^(a) and R^(a) ¹ when attached to anitrogen are taken together with the nitrogen to which they are attachedto form a 5 or 6 memnbered ring comprising carbon atoms and from 0-1additional heteroatoms selected from the group consisting of N, O, andS(O)_(p); R^(a) ² , at each occurrence, is independently selected fromC₁₋₄ alkyl, phenyl and benzyl; R^(b), at each occurrence, isindependently selected from C₁₋₆ alkyl, OR^(a), Cl, F, Br, ═O, —CN,NR^(a)R^(a) ¹ , C(O)R^(a), C(O)OR^(a), C(O)NR^(a)R^(a) ¹ ,S(O)₂NR^(a)R^(a) ¹ , S(O)_(p)R^(a) ² , and CF₃; R^(c), at eachoccurrence, is independently selected from C₁₋₆ alkyl, OR^(a), Cl, F,Br, ═O, —CN, NR^(a)R^(a) ¹ , C(O)R^(a), C(O)OR^(a), C(O)NR^(a)R^(a) ¹ ,S(O)₂NR^(a)R^(a) ¹ , S(O)_(p)R^(a) ¹ , CF₃, and C₃₋₆ carbocycle; R^(d),at each occurrence, is independently selected from C₁₋₆ alkyl, OR^(a),Cl, F, Br, ═O, —CN, NR^(a)R^(a) ¹ , C(O)R^(a), C(O)OR^(a),C(O)NR^(a)R^(a) ¹ , S(O)₂NR^(a)R^(a) ¹ , S(O)_(p)R^(a) ² , CF₃, and C₃₋₆carbocycle; R⁵, at each occurrence, is selected from C₁₋₆ alkylsubstituted with 0-2 R^(b), and C₁₋₄ alkyl substituted with 0-2 R^(e);R^(e), at each occurrence, is selected from phenyl substituted with 0-2R^(b) and biphenyl substituted with 0-2 R^(b); R⁶, at each occurrence,is selected from phenyl, naphthyl, C₁₋₁₀ alkyl-phenyl-C₁₋₆ alkyl-, C₃₋₁₁cycloalkyl, C₁₋₆ alkylcarbonyloxy-C₁₋₃ alkyl-, C₁₋₆alkoxycarbonyloxy-C₁₋₃ alkyl-, C₂₋₁₀ alkoxycarbonyl, C₃₋₆cycloalkylcarbonyloxy C₁₋₃ alky-, C₃₋₆ cycloalkoxycarbonyloxy-C₁₋₃alkyl-, C₃₋₆ cycloalkoxycarbonyl, phenoxycarbonyl,phenyloxycarbonyloxy-C₁₋₃ alkyl-, phenylcarbonyloxy-C₁₋₃ alkyl-, C₁₋₆alkoxy-C₁₋₆ alkylcarbonyloxy-C₁₋₃ alkyl-, [5-(C₁-C₅alkyl)-1,3-dioxa-cyclopenten-2-one-yl]methyl,[5-(R^(a))-1,3-dioxa-cyclopenten-2-one-yl]methyl,(5-aryl-1,3-dioxa-cyclopenten-2-one-yl]methyl, —C₁₋₁₀ alkyl-NR⁷R^(7a),—CH(R⁸)OC(═O)R⁹, and —CH(R⁸)OC(═O)OR⁹; R⁷ is selected from H and C₁₋₆alkyl, C₂₋₆ alkenyl, C₃₋₆ cycloalkyl-C₁₋₃ alkyl-, and phenyl-C₁₋₆alkyl-; R^(7a) is selected from H and C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₆cycloalkyl-C₁₋₃ alkyl-, and phenyl-C₁₋₆ alkyl-; R⁸ is selected from Hand C₁₋₄ linear alkyl; R⁹ is selected from H, C₁₋₆ alkyl substitutedwith 1-2 R^(f), C₃₋₆ cycloalkyl substituted with 1-2 R^(f), and phenylsubstituted with 0-2 R^(b); R^(f), at each occurrence, is selected fromC₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₁₋₅ alkoxy, and phenyl substituted with0-2 R^(b); p, at each occurrence, is selected from 0, 1, and 2; r, ateach occurrence, is selected from 0, 1, 2, 3, and 4; and, r¹, at eachoccurrence, is selected from 0, 1, 2, 3, and
 4. 3. A compound accordingto claim 2, wherein the compound is of formula IIIa;

or a stercoisomer or pharmaceutically acceptable salt form thereof,wherein; A is selected from —CO₂H, CH₂CO₂H, —CONHOH, —CONHOR⁵,—N(OH)CHO, and —N(OH)COR⁵; Z is phenyl substituted with 0-3 R^(b); U^(a)is absent or is selected from: O, NR^(a) ¹ , C(O), C(O)NR^(a) ¹ ,S(O)_(p), and S(O)_(p)NR^(a) ¹ ; X^(a) is absent or selected from C₁₋₄alkylene, C₂₋₄ alkenylene, and C₂₋₄ alkynylene Y^(a) is absent orselected from O and NR^(a) ¹ ; Z^(a) is pyridyl substituted with 0-3R^(c) or quinolinyl substituted with 0-3 R^(c); provided that Z, U^(a),Y^(a) and Z^(a) do not combine to form a N—N, N—O, O—N, O—O, S(O)_(p)—O,O—S(O)_(p) or S(O)_(p)—S(O)_(p) group; R¹ is selected from H, C₁₋₄alkyl, phenyl, and benzyl; R² is selected from Q, C₁₋₆ alkylene-Q, C₂₋₆alkenylene-Q, C₂₋₆ alkynylene-Q, (CR^(a)R^(a) ¹ )_(r) ₁ C(O)(CR^(a)R^(a)¹ )_(r)-Q, (CR^(a)R^(a) ¹ )_(r) ₁ C(O)O(CR^(a)R^(a) ¹ )_(r)-Q,(CR^(a)R^(a) ² )^(r) ¹ C(O)NR^(a)R^(a) ¹ , (CR^(a)R^(a) ² )_(r) ₁C(O)NR^(a)(CR^(a)R^(a) ¹ )_(r)-Q, and (CR^(a)R^(a) ¹ )_(r) ₁S(O)_(p)(CR^(a)R^(a) ¹ )_(r)-Q; Q is selected from H, and a C₃₋₆carbocycle substituted with 0-3 R^(d); R^(a), at each occurrence, isindependently selected from H, C₁₋₄ alkyl, phenyl and benzyl; R^(a1), ateach occurrence, is independently selected from H and C₁₋₄ alkyl; R^(a)² , at each occurrence, is independently selected from C₁₋₄ alkyl,phenyl, and benzyl; R^(b), at each occurrence, is independently selectedfrom C₁₋₄ alkyl, OR^(a), Cl, F, ═O, NR^(a)R^(a) ¹ , C(O)R^(a),C(O)OR^(a), C(O)NR^(a)R^(a) ¹ , S(O)₂NR^(a)R^(a) ¹ , S(O)_(p)R^(a) ² ,and CF₃; R^(c), at each occurrence, is independently selected from C₁₋₆alkyl, OR^(a), Cl, F, Br, ═O, NR^(a)R^(a) ¹ , C(O)R^(a), C(O)NR^(a)R^(a)¹ , S(O)₂NR^(a)R^(a) ¹ , S(O)_(p)R^(a) ² , and CF₃; R^(d), at eachoccurrence, is independently selected from C₁₋₆ alkyl, OR^(a), Cl, F,Br, ═O, NR^(a)R^(a) ¹ , C(O)R^(a), C(O)NR^(a)R^(a) ¹ , S(O)₂NR^(a)R^(a)¹ , S(O)_(p)R^(a) ² , CF₃, and phenyl; R⁵, at each occurrence, isselected from C₁₋₄ alkyl substituted with 0-2 R^(b), and C₁₋₄ alkylsubstituted with 0-2 R^(e); R^(c), at each occurrence, is selected fromphenyl substituted with 0-2 R^(b) and biphenyl substituted with 0-2R^(b); p, at each occurrence, is selected from 0, 1, and 2; r, at eachoccurrence, is selected from 0, 1, 2, 3, and 4; r¹, at each occurrence,is selected from 0, 1, 2, 3, and 4; and, s and s¹ combine to total
 3. 4.A compound according to claim 3, wherein the compound is of formula IVa

or a stereoisomer or pharmaceutically acceptable salt form thereof,wherein; Z is phenyl substituted with 0-3 R^(b); U^(a) is absent or isO; X^(a) is absent or is CH₂ or CH₂CH₂; Y^(a) is absent or is O; Z^(a)is pyridyl substituted with 0-3 R^(c), or quinolinyl substituted with0-3 R^(c); provided that Z, U^(a), Y^(a), and Z^(a) do not combine toform a N—N, N—O, O—N, or O—O group; R¹ is selected from H, CH₃, andCH₂CH₃; R² is selected from Q, C₁₋₆ alkylene-Q, C₂₋₆ alkynylene-Q,C(O)(CR^(a)R^(a) ¹ )_(r)-Q, C(O)O(CR^(a)R^(a) ¹ )_(r)-Q,C(O)NR^(a)(CR^(a)R^(a) ¹ )_(r)-Q, and S(O)_(p)(CR^(a)R^(a) ¹ )_(r)-Q; Qis selected from H, cycloprapyl substituted with 0-1 R^(d), cyclobutylsubstituted with 0-1 R^(d), cyclopentyl substituted with 0-1 R^(d),cyclohexyl substituted with 0-1 R^(d), and phenyl substituted with 0-2R^(d); R^(a), at each occurrence, is independently selected from H, CH₃,and CH₂CH₃; R^(a) ¹ , at each occurrence, is independently selected fromH, CH₃, and CH₂CH₃; R^(a) ² , at each occurrence, is independentlyselected from H, CH₃, and CH₂CH₃; R^(b), at each occurrence, isindependently selected from C₁₋₄ alkyl, OR^(a), Cl, F, ═O, NR^(a)R^(a) ¹, C(O)R^(a), C(O)OR^(a), C(O)NR^(a)R^(a) ¹ , S(O)₂NR^(a)R^(a) ¹ ,S(O)_(p)R^(a) ² , and CF₃; R^(c), at each occurrence, is independentlyselected from C₁₋₆ alkyl, OR^(a), Cl, F, Br, ═O, NR^(a)R^(a) ¹ ,C(O)R^(a), C(O)NR^(a)R^(a) ¹ , S(O)₂NR^(a)R^(a) ¹ , S(O)_(p)R^(a) ² ,and CF₃; R^(d), at each occurrence, is independently selected from C₁₋₆alkyl, OR^(a), Cl, F, Br, ═O, NR^(a)R^(a) ¹ , C(O)R^(a), C(O)NR^(a)R^(a)¹ , S(O)₂NR^(a)R^(a) ¹ , S(O)_(p)R^(a) ² , CF₃ and phenyl; p, at eachoccurrence, is selected from 0, 1, and 2; r, at each occurrence, isselected from 0, 1,2, and 3; r¹, at each occurrence, is selected from 0,1,2, and 3; and, s and s¹ combine to total
 3. 5. A compound according toclaim 2, wherein; A is selected from —CO₂H, CH₂CO₂H, —CONHOH, —CONHOR⁵,—N(OH)CHO, and —N(OH)COR⁵; ring B is piperidinyl or pyridinyl; Z isphenyl substituted with 0-3 R^(b); U^(a) is absent or is selected from:O, NR^(a) ¹ , C(O), C(O)NR^(a) ¹ , S(O)_(p), and S(O)_(p)NR^(a) ¹ ;X^(a) is absent or selected from C₁₋₂ alkylene, C₂₋₄ alkenylene, andC₂₋₄ alkynylene Y^(a) is absent or selected from O and NR^(a) ¹ ; Z^(a)is pyridyl substituted with 0-3 R^(c) or quinolinyl substituted with 0-3R^(c); provided that Z, U^(a), Y^(a), and Z^(a) do not combine to form aN—N, N—O, O—N, O—O, S(O)_(p)—O, O—S(O)_(p) or S(O)_(p)—S(O)_(p) group;R¹ is selected from H, C₁₋₄ alkyl, phenyl, and benzyl; R² is(CR^(a)R^(a) ¹ )_(r) ₁ O(CR^(a)R^(a) ¹ )_(r)-Q or (CR^(a)R^(a) ¹ )_(r) ₁NR^(a)(CR^(a)R^(a) ¹ )_(r)-Q; Q is selected from H, and a C₃₋₆carbocycle substituted with 0-3 R^(d); R^(a), at each occurrence, isindependently selected from H, C₁₋₄ alkyl, phenyl and benzyl; R^(a) ¹ ,at each occurrence, is independently selected from H and C₁₋₄ alkyl; R,a² , at each occurrence, is independently selected from C₁₋₄ alkyl,phenyl and benzyl; R^(b), at each occurrence, is independently selectedfrom C₁₋₄ alkyl, OR^(a), Cl, F, ═O, NR^(a)R^(a) ¹ , C(O)R^(a),C(O)OR^(a), C(O)NR^(a)R^(a) ¹ , S(O)₂NR^(a)R^(a) ¹ , S(O)_(p)R^(a) ² ,and CF₃; R^(c), at each occurrence, is independently selected from C₁₋₆alkyl, OR^(a), Cl, F, Br, ═O, NR^(a)R^(a) ¹ , C(O)R^(a), C(O)NR^(a)R^(a)¹ , S(O)₂NR^(a)R^(a) ¹ , S(O)_(p)R^(a) ² , and CF₃; R^(d), at eachoccurrence, is independently selected from C₁₋₆ alkyl, OR^(a), Cl, F,Br, ═O, NR^(a)R^(a) ¹ , C(O)R^(a), C(O)NR^(a)R^(a) ¹ , S(O)₂NR^(a)R^(a)¹ , S(O)_(p)R ² , CF₃ and phenyl; R⁵, at each occurrence, is selectedfrom C₁₋₄ alkyl substituted with 0-2 R^(b), and C₁₋₄ alkyl substitutedwith 0-2 R^(e); R^(e), at each occurrence, is selected from phenylsubstituted with 0-2 R^(b) and biphenyl substituted with 0-2 R^(b); p,at each occurrence, is selected from 0, 1, and 2; r, at each occurrence,is selected from 0, 1, 2, 3, and 4; and, r¹ at each occurrence, isselected from 0, 1, 2, 3, and
 4. 6. A compound according to claim 5,wherein; A is —CONHOH; ring B is piperidinyl or pyridinyl; Z is phenylsubstituted with 0-3 R^(b); U^(a) is absent or is O; X^(a) is absent oris CH₂ or CH₂CH₂; Y^(a) is absent or is O; Z^(a) is pyridyl substitutedwith 0-3 R^(c), or quinolinyl substituted with 0-3 R^(c); provided chatZ, U^(a), Y^(a), and Z^(a) do not combine to form a N—N, N—O, O—N, orO—O group; R¹ is selected from H, CH₃, and CH₂CH₃; R² is (CR^(a)R^(a) ¹)_(r) ₁ O(CR^(a)R^(a) ¹ )_(r)-Q or (CR^(a)R^(a) ¹ )_(r) ₁NR^(a)(CR^(a)R^(a) ¹ )_(r)-Q; Q is selected from H, cyclopropylsubstituted with 0-1 R^(d), cyclobutyl substituted with 0-1 R^(d),cyclopentyl substituted with 0-1R^(d); R^(a), at each occurrence, isindependently selected from H, CH₃, and CH₂CH₃; R^(a) ¹ , at eachoccurrence, is independently selected from H, CH₃, and CH₂CH₃; R^(a) ² ,at each occurrence, is independently selected from H, CH₃, and CH₂CH₃;R^(b), at each occurrence, is independently selected from C₁₋₄ alkyl,OR^(a), Cl, F, ═O, NR^(a)R^(a) ¹ , C(O)R^(a), C(O)OR^(a),C(O)NR^(a)R^(a) ¹ , S(O)₂NR^(a)R^(a) ¹ , S(O)_(p)R^(a) ² , and CF₃;R^(c), at each occurrence, is independently selected from C₁₋₆ alkyl,OR^(a), Cl, F, Br, ═O, NR^(a)R^(a) ¹ , C(O)R^(a), C(O)NR^(a)R^(a) ¹ ,S(O)₂NR^(a)R^(a) ¹ , S(O)_(p)R^(a) ² , and CF₃; R^(d), at eachoccurrence, is independently selected from C₁₋₆ alkyl, OR^(a), Cl, F,Br, ═O, NR^(a)R^(a) ¹ , C(O)R^(a), C(O)NR^(a)R^(a) ¹ , S(O)₂NR^(a)R^(a)¹ , S(O)_(p)R^(a) ² , CF₃ and phenyl; p, at each occurrence, is selectedfrom 0, 1, and 2; r, at each occurrence, is selected from 0, 1, 2, and3; and, r¹, at each occurrence, is selected from 0, 1, 2, and
 3. 7. Acompound according to claim 1, wherein the compound is selected from thegroup:(3S,4S)-N-hydroxy-4-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]aminol-3-piperidinecarboxamide;(3S,4R)-N-hydroxy-4-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-3-piperidinecarboxamide;(3S,4R)-1-[(butoxy)carbonyl]-N-hydroxy-4-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-3-piperidinecarboxamide;(3S,4R)-N-hydroxy-1-[[(1-methylethyl)oxy]carbonyl]-4-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-3-piperidinecarboxamide;(3S,4R)-N-hydroxy-1-(methylsulfonyl)-4-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-3-piperidinecarboxamide;(3S,4R)-N-hydroxy-4-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-1-(phenylsulfonyl)-3-piperidinecarboxamide;(3S,4R)-1-acetyl-N-hydroxy-4-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-3-piperidinecarboxamide;(3S,4R)-1-benzoyl-N-hydroxy-4-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-3-piperidinecarboxamide;(3S,4R)-1-(2,2-dimethylpripionyl)-N-hydroxy-4-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-3-piperidinecarboxamide;(3S,4R)-1-(3,3-dimethylbutanoyl)-N-hydroxy-4-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-3-piperidinecarboxamide;(3S,4R)-N-hydroxy-4-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-1-(4-morpholinecarbonyl)-3-piperidinecarboxamide;(3S,4R)-1-(dimethylcarbamyl)-N-hydroxy-4-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-3-piperidinecarboxamide;(3S,4R)-N-hydroxy-1-methyl-4-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-3-piperidinecarboxamide;(3S,4R)-1-ethyl-N-hydroxy-4-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-3-piperidinecarboxamide;(3S,4R)-N-hydroxy-4-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-1-propyl-3-piperidinecarboxamide;(3S,4R)-N-hydroxy-1-(1-methylethyl)-4-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-3-piperidinecarboxamide;(3S,4R)-1-(cyclopropylmethyl)-N-hydroxy-4-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-3-piperidinecarboxamide;(3S,4R)-1-(2,2-dimethylpropyl)-N-hydroxy-4-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-3-piperidinecarboxamide;(3S,4R)-1-benzyl-N-hydroxy-4-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-3-piperidinecarboxamide;(3S,4S)-1-[[(1,1-dimethylethyl)oxy]carbonyl]-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide;(3R,4S)-1-[[(1,1-dimethylethyl)oxy]carbonyl]-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide;(3R,4S)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide;(3S,4S)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide;(3S,4S)-N-hydroxy-1-[[(2-methylpropyl)oxy]carbonyl]-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide;(3S,4S)-N-hydroxy-1-(methoxycarbonyl)-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide;(3S,4S)-N-hydroxy-1-[(1-methylethoxy)carbonyl]-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide;(3S,4S)-N-hydroxy-1-(methylsulfonyl)-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide(3S,4S)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-1-(phenylsulfonyl)-4-piperidinecarboxamide;(3S,4S)-1-(3,3-dimethylbutanoyl)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide;(3S,4S)-1-(2,2-dimethylpropionyl)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide;(3S,4S)-1-benzoyl-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide;(3S,4S)-1-[(pyridin-3-yl)carbonyl]-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide;(3S,4S)-1-(dimethylcarbamyl)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide;(3S,4S)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-1-(4-morpholinecarbonyl)-4-piperidinecarboxamide;(3S,4S)-1-[(1,1-dimethylethyl)carbamyl]-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide;(3S,4S)-N-hydroxy-1-methyl-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide;(3S,4S)-1-ethyl-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide;(3S,4S)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-1-propyl-4-piperidinecarboxamide;(3S,4S)-N-hydroxy-1-(1-methylethyl)-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide;(3S,4S)-1-cyclobutyl-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide;(3S,4S)-1-butyl-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide;(3S,4S)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-1-(2-methylpropyl)-4-piperidinecarboxamide;(3S,4S)-1-(cyclopropylmethyl)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide;(3S,4S)-1-(2,2-dimethylpropyl)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide;(3S,4S)-1-cyclopentyl-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide;(3S,4S)-1-benzyl-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide;(3S,4S)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-1-(trans-3-phenyl-2-propenyl)-4-piperidinecarboxamide;(3S,4S)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-1-phenyl-4-piperidinecarboxamide;(3R,4S)-1-(2,2-dimethylpropionyl)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide;(3R,4S)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-1-methyl-4-piperidinecarboxamide;(3R,4S)-1-(dimethylcarbamyl)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide;(3S,4S)-1-hexyl-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide;(3S,4S)-1-(2-fluoroethyl)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide;(3S,4S)-1-(2,2-difluoroethyl)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide;(3S,4S)-N-hydroxy-1-(1-methylpropyl)-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide;(3S,4S)-1-(1-ethylpropyl)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide;(3S,4S)-1-[1-[[(1,1-dimethylethyl)oxy]carbonyl]-4-tetrahydropiperidinyl]-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide;(3S,4S)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-1-(4-tetrahydropiperidinyl)-4-piperidinecarboxamide;(3S,4S)-1-(1,1-dimethyl-2-propynyl)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide;(3S,4S)-N-hydroxy-1-(1-methylethyl)-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-1-oxo-4-piperidinecarboxamide;(3S,4S)-N-hydroxy-1-(1-methylethyl)-3-[[[4-[(2-methyl-1-oxo-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide;(3S,4S)-N-hydroxy-1-(1-methylethyl)-3-[[[4-[(2-methyl-1-oxo-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-1-oxo-4-piperidinecarboxamide;(3S,4S)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-1-[2-(4-morpholinyl)-2-oxoethyl]-4-piperidinecarboxamide;(3S,4S)-1-[2-(N,N-dimethylamino)-2-oxoethyl]-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide;(3S,4S)-1-(t-butylsulfonyl)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide;(3S,4S)-1-(t-butylsulfonyl)-N-hydroxy-3-[[[4-[(2-methyl-1-oxo-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide;(3S,4S)-1-(benzenesulfonyl)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide;(3S,4S)-1-(t-butylsulfinyl)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide;(3S,4S)-N-hydroxy-1-(2-hydroxylethyl)-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide;(3S,4S)-1-[2-[[[(1,1-dimethylethyl)oxy]carbonyl]amino]ethyl]-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide;(3S,4S)-1-(2-aminoethyl)-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide;(3S,4S)-1-[2-(N,N-dimethylamino)ethyl]-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide;(3S,4S)-1-[(2S)-2-aminopropyl]-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide;(3S,4S)-1-[(2R)-2-amino-3-hydroxypropyl]-N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-4-piperidinecarboxamide;(3S,4R)-N-hydroxy-1-(2-hydroxylethyl)-4-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-3-piperidinecarboxamide;(3S,4R)-1-(2-aminoethyl)-N-hydroxy-4-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-3-piperidinecarboxamide;(3S,4R)-1-cyclobutyl-N-hydroxy-4-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]-3-piperidinecarboxamide;(3S,4S)-1-tert-butyl-N-hydroxy-3-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-4-piperidinecarboxamide;tert-butyl2-[(3S,4S)-4-[(hydroxyamino)carbonyl]-3-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)piperidinyl]-2-methylpropanoate2-[(3S,4S)-4-[(hydroxyamino)carbonyl]-3-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)piperidinyl]-2-methylpropanoicacid; methyl2-[(3S,4S)-4-[(hydroxyamino)carbonyl]-3-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)piperidinyl]-2-methylpropanoate;(3S,4S)-N-hydroxy-3-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-1-[2-(4-morpholinyl)-2-oxoethyl]-4-piperidinecarboxamide;(3S,4S)-1-[2-(dimethylamino)-2-oxoethyl]-N-hydroxy-3-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-4-piperidinecarboxamide;(3S,4S)-1-(1,1-dimethyl-2-propenyl)-N-hydroxy-3-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-4-piperidinecarboxamide;(3S,4S)-N-hydroxy-3-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-1-tert-pentyl-4-piperidinecarboxamide;(3S,4S)-N-hydroxy-3-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-1-(2-propynyl)-4-piperidinecarboxamide;(3S,4S)-1-allyl-N-hydroxy-3-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-4-piperidinecarboxamide;(3S,4S)-N-hydroxy-1-(1-methyl-2-propynyl)-3-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-4-piperidinecarboxamide;(3S,4S)-N-hydroxy-1-(1-methyl-2-propenyl)-3-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-4-piperidinecarboxamide;(5S)-N-hydroxy-5-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-2-oxo-4-piperidinecarboxamide;(3S,4S)-N-hydroxy-3-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-2-oxo-4-piperidinecarboxylate;(3S,4S)-N-hydroxy-3-({4-[(2-methyl-3-pyridinyl)methoxy]benzoyl}amino)-4-piperidinecarboxamide;N-hydroxy-3-({6-[(2-methyl-4-quinolinyl)methoxy]-1-naphthoyl}amino)-4-piperidinecarboxamide;or a pharmaceutically acceptable salt form thereof.
 8. A pharmaceuticalcomposition, comprising: a pharmaceutically acceptable carrier and atherapeutically effective amount of a compound according to claim 1 or apharmaceutically acceptable salt form thereof.
 9. A method of treating adisease or condition selected from Crohn's disease, psoriasis, psoriaticarthritis, and rheumatoid arthritis, comprising administering to themammal in need of such treatment a therapeutically effective amount of acompound according to claim
 1. 10. A pharmaceutical composition,comprising: a pharmaceutically acceptable carrier and a therapeuticallyeffective amount of a compound according to claim 2 or apharmaceutically acceptable salt form thereof.
 11. A pharmaceuticalcomposition, comprising: a pharmaceutically acceptable carrier and atherapeutically effective amount of a compound according to claim 3 or apharmaceutically acceptable salt form thereof.
 12. A pharmaceuticalcomposition, comprising: a pharmaceutically acceptable carrier and atherapeutically effective amount of a compound according to claim 4 or apharmaceutically acceptable salt form thereof.
 13. A pharmaceuticalcomposition, comprising: a pharmaceutically acceptable carrier and atherapeutically effective amount of a compound according to claim 5 or apharmaceutically acceptable salt form thereof.
 14. A pharmaceuticalcomposition, comprising: a pharmaceutically acceptable carrier and atherapeutically effective amount of a compound according to claim 6 or apharmaceutically acceptable salt form thereof.
 15. A pharmaceuticalcomposition, comprising: a pharmaceutically acceptable carrier and atherapeutically effective amount of a conipound according to claim 7 ora pharmaceutically acceptable salt form thereof.
 16. A method oftreating a disease or condition selected from Crohn's disease,psoriasis, psoriatic arthritis, and rheumatoid arthritis, comprisingadministering to the mammal in need of such treatment a therapeuticallyeffective amount of a compound according to claim
 2. 17. A method oftreating a disease or condition selected from Crohn's disease,psoriasis, psoriatic arthritis, and rheumatoid arthritis, comprisingadministering to the mammal in need of such treatment a therapeuticallyeffective amount of a compound according to claim
 3. 18. A method oftreating a disease or condition selected from Crohn's disease,psoriasis, psoriatic arthritis, and rheumatoid arthritis, comprisingadministering to the mammal in need of such treatment a therapeuticallyeffective amount of a compound according to claim
 4. 19. A method oftreating a disease or condition selected from Crotm's disease,psoriasis, psoriatic arthritis, and rheumatoid arthritis, comprisingadministering to the mammal in need of such treatment a therapeuticallyeffective amount of a compound according to claim
 5. 20. A method oftreating a disease or condition selected from Crohn's disease,psoriasis, psonatic arthritis, and rheumatoid arthritis, comprisingadministering to the mammal in need of such treatment a therapeuticallyeffective amount of a compound according to claim
 6. 21. A method oftreating a disease or condition selected from Crohn's disease,psoriasis, psonatic arthritis, and rheumatoid arthritis, comprisingadministering to the mammal in need of such treatment a therapeuticallyeffective amount of a compound according to claim 7.